1-Alkoximino-2-(ω-substituted-alkyl)-2-cyclopentenes

ABSTRACT

This disclosure describes certain 1-alkoximino-2-(ω-substituted-alkyl)-2-cyclopentenes useful as intermediates for the preparation of homologues, analogues, congeners, and derivatives of 9-oxo-13-trans-prostenoic acid and of 9-hydroxy-13-trans-prostenoic acid which have antimicrobial activity and prostaglandin-like hypotensive activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 552,686 filed Feb. 24, 1975now U.S. Pat. No. 4,006,179, which is a division of application Ser. No.480,908, filed June 19, 1974 now U.S. Pat. No. 3,884,953, which is adivision of application Ser. No. 335,842, filed Feb. 26, 1973, now U.S.Pat. No. 3,836,581 which is a continuation-in-part of application Ser.No. 208,951, filed Dec. 16, 1971, now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds, and more particularly,is concerned with novel intermediates for a class of compounds relatedto the natural prostaglandins. The novel compounds of the presentinvention may be represented by the following general formula: ##STR1##wherein n is an integer from 3 to 8, inclusive; R is a lower alkyl grouphaving up to four carbon atoms; and Q is selected from the groupconsisting of hydroxy, lower alkanesulfonyloxy, p-toluenesulfonyloxy,chloro, bromo, iodo, lower acyloxy, cyano, carboxy, lower carboalkoxy,dicarboxymethyl, di(lower carboalkoxy) methyl, and moieties of theformulae: ##STR2## wherein R is a lower alkyl group and R₁ is selectedfrom the group consisting of lower alkyl, fluoro and phenyl. Suitablelower alkyl, lower alkane, lower acyloxy, and lower carboalkoxy groupscontemplated by the present invention are those having up to four carbonatoms such as, for example, methyl, ethyl, secbutyl, methane, ethane,n-propane, acetyloxy, propionyloxy, isobutyryloxy, carbomethoxy,carboethoxy, carbo-n-propoxy, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The prostaglandins are a family of closely related compounds which havebeen obtained from various animal tissues, and which stimulate smoothmuscle, lower arterial blood pressure, antagonize epinephrine-inducedmobilization of free fatty acids, and have other pharmacological andautopharmacological effects in mammals. See Bergstrom et al., J. Biol.Chem. 238, 3555 (1963) and Horton, Experienta 21, 113 (1965) andreferences cited therein. All of the so-called natural prostaglandinsare derivatives of prostanoic acid: ##STR3## The hydrogen atoms attachedto C-8 and C-12 are in trans configuration. The novel compounds of thepresent invention are useful as intermediates for the preparation ofhomologues, analogues, congeners, and derivatives of9-oxo-13-trans-prostenoic acid and of 9-hydroxy-13-trans-prostenoic acidhaving antimicrobial activity and prostaglandin-like hypotensiveactivity as is set forth hereinafter.

The novel compounds of the present invention may be readily preparedfrom 2-carbethoxycyclopentanone in accordance with the reaction schemesset forth in Flowsheets A through E. In particular, the requisite2-(ω-carbethoxyalkyl)cyclopent-2-en-1-one intermediates (VIII) may beprepared in accordance with the following reaction scheme: ##STR4##wherein n is as hereinabove defined and X is iodo or bromo. Inaccordance with this reaction scheme, the cyclopent-2-en-1-ones (VIII)are developed by first converting 2-carbethoxycyclopentanone (I) to thesodium enolate thereof by means of sodium hydride in dimethoxyethane andthen treating the sodium enolate with an ethyl ω-haloalkanoate (II).There is thus obtained the corresponding2-carbethoxy-2-(ω-carbethoxyalkyl)cyclopentanone (III) which is thenhydrolzed and decarboxylated to afford the2-(ω-carboxyalkyl)cyclopentanone (IV). This acid is then esterified withethanol whereby the 2-(ω-carbethoxyalkyl)cyclopentanone (V) is obtained.The reaction conditions for carrying out the above sequence of reactionsare well known in the art. The conversion of the cyclopentanone (V) tothe enol acetate (VI) is effected by heating with acetic anhydride inthe presence of p-toluenesulfonic acid. Preparation of the enol acetate(VI) usually requires heating for a period of from about eight tothirty-six hours. During this period, it is preferable to allowby-product acetic acid to distill out in order to force the reaction tocompletion. The bromination of the enol acetates (VI) to the2-bromocyclopentanones (VII) is preferably carried out in a two phasesystem as follows. A solution of bromine in chloroform is added to arapidly stirred mixture of a solution of the enol acetate (VI) inchloroform and an aqueous solution of an acid acceptor such as calciumcarbonate or soda ash. This addition is carried out at 0°-5° C. over aperiod of about half an hour, stirring is continued for an additionalperiod of about half an hour to a few hours, and the product (VII) isthen isolated by standard procedures. The dehydrobromination of the2-bromocyclopentanones (VII) is preferably carried out indimethylformamide with a mixture of lithium bromide and lithiumcarbonate at the reflux temperature for a period of about 30 minutes toan hour or so. The so formed cyclopent-2-en-1-ones (VIII) are alsoisolated by standard procedures well known in the art.

The required cyclopent-2-en-1-one intermediates wherein the side-chainhas a substituent R₁ alpha to the carboxy or carboalkoxy function may beprepared in accordance with the following reaction scheme: ##STR5##wherein n and R and R₁ are as hereinabove defined; and X is chloro,bromo or iodo. In accordance with this reaction scheme, the2-(ω-carbethoxyalkyl)cyclopent-2-en-1-ones (IX) are converted to thecorresponding 1-alkoximino-2-(ω-carbethoxyalkyl)-2-cyclopentenes (X) bytreatment with an alkoxyamine. With the ring carbonyl function thusblocked it is possible to effect a preferential reduction of the estergroup by treatment with diisobutylaluminum hydride. Th resulting alcohol(XI) is converted to a tosylate derivative (XII), which undergoesdisplacement on treatment with the sodium salt of a dialkyl substitutedmalonate (XIII) to provide the disubstituted malonate derivatives (XIV).Sometimes it is preferable to conduct the malonate displacement on ahalide derivative (XIIa), which is readily preparable from the tosylate(XII) by displacement with chloride, bromide or iodide. Among thesubstituted dialkyl malonates (XIII) which can be utilized are diethylethylmalonate, diethyl fluoromalonate and diethyl phenylmalonate.Hydrolysis and decarboxylation as well as concomittant cleavage of thealkoximino blocking group provides the desired2-(ω-carboxy-α-substituted alkyl)cyclopent-2-en-1-ones (XV), which arereadily converted to the corresponding ester (XVI) by the usual Fisherprocedure or via the acid chloride. Hydrolysis without decarboxylationand concomittant cleavage of the alkoximino blocking group provides theintermediate 1-alkoximino-2-(ω-dicarboxy-α-substituted-loweralkyl)-2-cyclopentenes (XVII). These dicarboxylic acids can bedecarboxylated to the corresponding alkoximino monocarboxylic acid;alkoxime hydrolysis then provides (XV).

The requisite 2-(ω-carboalkoxy-3-oxa-alkyl)-cyclopent-2-en-1-ones(XXIII) and 2-(ω-carboalkoxy-3-thia-alkyl)cyclopent-2-en-1-ones (XXVII)may be prepared in accordance with the reaction scheme of Flowsheet C,wherein n and R are as hereinbefore defined. ##STR6##

In accordance with the reaction scheme shown in Flowsheet C, for thepreparation of the oxa derivative (XXIII), an appropriate2-(ω-carbethoxyalkyl)cyclopent-2-en-1-one (XVIII) is converted to thecorresponding alkoxime (XIX), the ester function of which is thenpreferentially reduced with diisobutylaluminum hydride to afford thealkoxime alcohol (XX). The alcohol (XX) is converted on treatment withn-butyl lithium to the lithio alcoholate, which then is O-alkylated byreaction with an alkyl bromoacetate to provide (XXI). Hydrolysis withacetone-aqueous hydrochloric acid furnishes the deblocked keto-acid(XXII), which is then re-esterified with an alkanol in the presence ofp-toluenesulfonic acid to give the required2-(ω-carboalkoxy-3-oxa-alkyl)cyclopent-2-en-1-one (XXIII). O-Alkylationcan also be accomplished by treatment of the lithio alcoholate of (XX)with the sodium or other metal salt of chloroacetic acid, in which casethe free carboxylix acid corresponding to ester (XXI) is obtained.Hydrolysis as for (XXI) provides the keto acid (XXII).

The preparation of the thia derivatives (XXVII), proceeds from theintermediate alcohol (XX), which after conversion to the tosylateintermediate (XXIV) and reaction with the sodium salt of an alkylmercaptoacetate furnishes intermediate (XXV). Deblocking of XXV withacetone-aqueous hydrochloric acid provides the keto-acid (XXVI), whichon re-esterification with an alkanol gives the required2-(ω-carboalkoxy-3-thia-alkyl)cyclopent-2-en-1-ones (XXVII).

By the procedure outlined in Flowsheet D below (wherein n and R are ashereinabove defined), it is also possible to homologate the originalside chain by one or two carbon atoms. Thus, the1-alkoximino-2-(ω-hydroxyalkyl)cyclopentene (XXVIII) prepared asdescribed above (compound XX in Flowsheet C and compound XI in FlowsheetB) is converted to the mesylate (XXIX), which on treatment with cyanideion undergoes displacement of the mesyloxy function to give nitrile(XXX), alkaline hydrolysis of

which provides acid (XXXI). The alkoximino group is then cleaved withacid and the carboxylic acid function is esterified to providecyclopentenone (XXXII) bearing a side chain homologated by one carbonatom relative to cyclopentenone (XVIII) of Flowsheet C. ##STR7##

Two carbon homologation to (XXXVI) is achieved via reaction of mesylate(XXIX) with a dialkyl sodio malonate to give (XXXIII), which ishydrolyzed to the substituted malonic acid (XXXIV) and decarboxylated to(XXXV). Cleavage of the alkoximino function followed by esterificationprovides the desired (XXXVI).

The mono-substituted malonate (XXXIII) of Flowsheet D also can beutilized for the preparation of certain of the compounds of thisinvention wherein the carboalkoxy group has an α-substituent. Thus,malonate (XXXIII) is converted to a sodio salt by treatment with sodiumhydride, sodium alkoxide, or the like. Reaction of the salt with loweralkylating agents, diphenyliodonium halides, or perchloryl fluorideresults in the introduction of lower alkyl, phenyl, or fluoro groups,respectively, to give compound (XIV) of Flowsheet B wherein R₁ is loweralkyl, phenyl, or fluoro.

An alternate preparation of the key2-(ω-hydroxyalkyl)cyclopent-2-en-1-one alkoxime (XLVI) (XI, XX, andXXVII in Flowsheets B, C, and D, respectively) is available according tothe sequence of the following Flowsheet E, wherein n, R and X are ashereinabove defined. This is essentially the method of Flowsheet Aexcept that 2-carbethoxycyclopentanone (XXXVII) is alkylated with1-halo-ω-acyloxyalkane (XXXVIII) to give (XXXIX). This step is followedby decarbalkoxylation, enol alkanoate formation, bromination anddehydrobromination to provide the2-(ω-alkanoyloxyalkyl)cyclopent-2-en-1-one (XLIV), which is thenconverted to the alkoxime (XLV). De-O-acylation of (XLV) provides thefree alcohol (XLVI). ##STR8##

The conjugate 1,4-addition of an alanate salt (XLVIII) to a2-substituted cyclopent-2-en-1-one (XLVII), obtained by hydrolysis ofthe corresponding 1-alkoximino derivatives of the present invention,provides the 9-oxo-13-trans-prostenoic acid derivatives (XLIX and L) asset forth in the following Flow-sheet F: ##STR9## wherein Z is adivalent radical selected from the group consisting of --(CH₂)_(n) --,--(CH₂)_(n) --O--CH₂ --, --(CH₂)_(n) --S--CH₂ --, ##STR10## wherein nand R₁ are as hereinbefore defined; R' is a lower alkyl group,preferably methyl or n-butyl; and R₂ is a straight chain alkyl grouphaving from 3 to 10 carbon atoms, a straight chain alkyl group havingfrom 2 to 6 carbon atoms and having one branched methyl group, astraight chain alkenyl group having from 4 to 6 carbon atoms, or astraight chain ω-chloroalkyl group having from 3 to 6 carbon atoms. Thecompounds (XLIX) are readily prepared by the conjugate 1,4-addition ofan alanate salt (XLVIII) to a 2-substituted cyclopent-2-en-1-one(XLVII). The yields of this operation are usually high and a cleanproduct, uncontaminated with 1,2-addition product, is usually obtained.Furthermore, the transfer of the alkene group is effected with retentionof the trans-configuration of the hydrogen atoms attached to the doublebond, and no reaction is noted at the carbethoxy function of (XLVII).Another noteworthy aspect of this reaction is that it does not require acatalyst. The alanate salts (XLVIII) are conveniently prepared by thereaction of an appropriate 1-alkyne (R₂ --C.tbd.CH) withdiisobutylaluminum hydride, followed by reaction with a lower alkyllithium derivative, preferably methyl lithium or n-butyl lithium.Suitable 1-alkynes which may be thus employed are, for example,1-pentyne, 1-hexyne, 1-decyne, 1-hendecyne, 1-dodecyne,3-methyl-1-butyne, 1-heptyne, 1-oxtyne, 1-nonyne, 5-methyl-1-hexyne,7-methyl-1-octyne, 7-methyl-1-nonyne, 3-methyl-1-octyne,4-methyl-1-octyne, oct-5-en-1-yne, hept-5-en- 1-yne, hex-4-en-1-yne,5-chloro-1-pentyne, 6-chloro-1-hexyne, 7-chloro-1-heptyne,8-chloro-1-octyne, etc. The reaction of the 1-alkyne withdiisobutylaluminum hydride cleanly provides the trans-double bond and ispreferably carried out in an inert solvent such as benzene, toluene, andthe like at temperatures in the range of 40°-60° C. for several hours.The solvent is removed in vacuo and the subsequent reaction with methylor n-butyl lithium is preferably carried out in an ether-type solventsuch as diethyl ether, dibutyl ether, tetrahydrofuran, and the like.This reaction is rapid and is preferably carried out at 0°-10° C. withcooling. The conjugate 1,4-addition of the resulting alanate salt(XLVIII) to the cyclopent-2-en-1-one (LXVII) is preferably carried outat ambient temperatures for a period of 12 to 24 hours. This reaction isalso best carried out in an ether-type solvent such as diethyl ether,dibutyl ether, tetrahydrofuran, and the like. The intermediatealanate-enolate adduct is then hydrolyzed in situ with dilutehydrochloric acid with cooling, and the products (XLIX) are isolated inthe usual manner well known in the art. The conversion of the esters(XLIX) to the acids (L) is readily accomplished by mild saponificationprocedures such as in 0.5N aqueous-methanolic KOH at room temperaturefor 20-48 hours.

Other 9-oxo-13-trans-prostenoic acid derivatives maybe prepared asillustrated by the following flowsheets wherein p is an integer from 2to 4, inclusive; 9 is an integer from 3 to 6, inclusive, R₃ is a loweralkyl group having up to 3 carbon atoms; R₄ is hydrogen or lower alkyl;R₅ is hydrogen or lower alkyl; and R₄ and R₅ taken together with theN(nitrogen) is pyrrolidino, morpholino or piperidino.

    __________________________________________________________________________    FLOWSHEET G                                                                   __________________________________________________________________________     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                     ##STR20##                                                                       In Flowsheet G, treatment of the chloro derivative (LI) with sodium        iodide provides the iodo derivative (LII), which on treatment with the        sodium salt of an alkyl mercaptan furnishes the thia derivative (LIII),       saponification of which give (LVI). Sulfur-oxidation of (LIII) with an        equivalent of sodium metaperiodate affords the sulfoxide ester (LIV),     

When the iodo derivative (LII) is treated with diethyl sodio malonatethe triester (LVII) results, which on saponification provides thecorresponding triacid, heating of which in refluxing xylene causesdecarboxylation of the substituted malonic acid to give the diacid(LVIII).

For some displacement reactions it is preferable to protect the ringketone function in (LII). This can be accomplished by conversion to theethylene ketal derivatives (LIX). Treatment of (LIX) with pyrrolidinegives the pyrrolidino derivative (LX), acid hydrolysis of the ketalblocking group then gives the keto-aminoacid (LXI). Treatment of iodoketal (LIX) with a metal alkoxide provides a mixture of the oxaderivative (LXII) and the diene (LXIII), separable by chromatography.Ketal hydrolysis with acetone and p-toluenesulfonic acid of these twoketal esters gives the corresponding keto ester (LXIV) and (LXVI)respectively, saponification of which furnishes the keto acids (LXV) and(LXVII), respectively.

Additional transformations are illustrated in Flowsheet H, wherein q andZ are as hereinabove defined, R" is hydrogen or lower alkyl, R'" islower alkyl, and R" and R'" taken together with the N(itrogen) ispyrrolidino, piperidino or morpholino. ##STR21##

In accordance with Flowsheet H, treatment of the chloroketone (LXVIII)with sodium iodide in refluxing acetone produces the iodoketo ester(LXX), mild saponification of which provides the corresponding acid(LXIX). Treatment of the iodoketone ester with thiourea, followed bytreatment of the intermediate thiuronium salt with an equivalent ofalkali affords the mercapto ketoester (LXXI), which on saponificationgives the corresponding acid (LXXII). Other transformations arepreferably carried out after blocking the ring keto function as anethylene ketal, thus the preparation of compound (LXXII). Reaction ofketal (LXXII) with potassium phthalimide in dimethylformamide(preferably at about 70° C. for about two hours) furnishes thephthalimido ketal (LXXIV). Deblocking of (LXXIV) to the amino ketoacid(LXXVI) is accomplished by first treating with potassium hydroxide inaqueous methanol followed by heating at reflux for about eighteen hourswith aqueous hydrochloric acid. Substituted amino groups can beintroduced by treating iodo ketal (LXXII) with various amines ##STR22##to give (LXXV) followed by ester and ketal hydrolysis to the aminoketoacids (LXXVII).

Additional transformations are illustrated in Flowsheet J, wherein p andR₂ are as defined hereinbefore. The synthesis of those compoundsembodying at the same time Z as ##STR23## can be accomplished bytransformations of (LXXX) or (LXXXI) wherein R₂ contains anω-chloroalkyl group in the manner described above in Flowsheets G and H.

In Flowsheet J, which follows, the ring carbonyl function of the2-(carbethoxymethyl)cyclopentanone (LXXVIII) is blocked by conversion tothe ketal (LXXIX). The ester function in (LXXIX) is then reduced to analdehyde by treatment with diisobutylaluminium hydride. This reaction ispreferably carried out by addition of one molecular equivalent of thisreagent to a solution of ester (LXXIX) in hexane or other hydrocarbonsolvent, cooled to -78° C. After about 2.5 hours at this temperature theentire reaction mixture is poured quickly into aqueous excess mineralacid, and the product aldehyde (LXXXI) is obtained upon immediatework-up in the usual way. The aldehyde (LXXXI) is then converted to(LXXX) by addition of (LXXXI) to the ylid prepared from(ω-carboxyalkyl)triphenyl phosphonium bromide and two molecularequivalents of sodium hydride in anhydrous dimethylsulfoxide. The use ofdimethylsulfoxide as a solvent for this reaction leads to thepredominant formation of the desired cis double bond in product (LXXX).The ketal blocking group in (LXXX) is then cleaved by treatment withacetone and p-toluenesulfonic acid producing the keto acid. ##STR24##

The various 9-hydroxy derivatives are prepared by reduction of thecorresponding 9-keto ester or by subsequent transformations of thereduction product of the type recorded in Flowsheets G and H.Saponification of the ester provides the corresponding 9-hydroxy acids.The reduction is preferably carried out in the usual manner with sodiumborohydride in ethanol as a solvent. The prostanoic acids areconvertable to the corresponding ester by first treating with thionylchloride and then reacting the resulting acid chloride with anappropriate alcohol in the presence of an acid acceptor, e.g.,diethylamine. The new ester can then undergo the transformationsillustrated in Flowsheets G and H.

All of the prostaglandin-like compounds can be isolated and purified byconventional methods. Isolation can be accomplished, for example, bydilution of the reaction mixture with water, extraction with awater-immiscible solvent such as methylene chloride, ethyl acetate,benzene, cyclohexane, ether, toluene and the like, chromatography,adsorption on ion-exchange resins, distillation, or a combination ofthese. Purification of the compounds can be accomplished by means knownin the art for the purification of prostaglandins and lipids, fattyacids, and fatty esters. For example, reverse phase partitionchromatography, countercurrent distribution, adsorption chromatographyon acid washed Florisil ® (synthetic magnesium silicate) and acid washedsilica gel, preparative paper chromatography, preparative thin layerchromatography, chromatography over silver loaded cation exchangeresins, and combinations thereof can be used effectively to purify theprostaglandin-like compounds.

The racemic prostaglandin-like compounds can be resolved into theiroptically active components by a number of methods of resolution wellknown in the art. For example, compounds L, LV, LVI, LVIII, LXI, LXV,LXVII, LXIX, LXXIII, LXXVI, LXXVII and LXXXII can all be obtained asfree acids. These acids can be treated with an optically active basesuch as cinchonine, quinine, brucine, d- or 1-α-phenylethylamine and thelike to produce diastereoisomeric salts which can be separated bycrystallization. Alternatively, the acid may be esterified with anoptically active alcohol, e.g., d- or 1-menthol, estradiol 3-acetate,etc., and the diastereoisomeric esters then resolved.

Resolution of the racemic prostaglandin-like compounds can also beaccomplished by reverse phase and absorption chromatography on anoptically active support and adsorbent and by selective transformationof one isomer with a biologically-active prostaglandin transformingsystem. Such transformations can be carried out by incubation ofperfusion using methods well established in the art, followed byisolation and recovery of the isomer resistant to the metabolictransformation applied. The prostaglandin-like compounds are obtainableas yellow oils having characteristic absorption spectra. They arerelatively soluble in common organic solvents such as ethanol, ethylacetate, dimethylformamide, and the like.

The prostaglandin-like compounds are useful as hypotensive agents andtheir prostaglandin-like hypotensive activity was demonstrated in thefollowing test procedure. This procedure is a modification of thetechnique described by Pike et al., Prostaglandins, Novel Symposium 2,Stockholm, June, 1966; p. 165.

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250grams in weight were fastened to rat broads in a supine position bymeans of canvas vests and limb ties. The femoral area was infiltratedsubcutaneously with lidocaine and the iliac artery and vein were exposedand cannulated. Arterial blood pressure (systolic/diastolic) wasrecorded using a Statham P₂₃ Db pressure transducer-Offner dynographsystem. To obtain a stable blood pressure, the animals were anesthetizedbefore use with pentobarbital, 30 mg./kg. of body weight intravenously,and also were given hexamethonium bitartrate, 2 mg./kg. of body weightintravenously. The test compounds were prepared by ultrasonic dispersionin a saline-Tween 80 ® vehicle. A constant intravenous dose volume of0.5 ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg.of body weight. Increasing or decreasing doses were selected dependingon the dose response obtained. In Table I below are set forth theminimal doses required to produce a decrease of about 10 mm. indiastolic blood pressure for typical compounds.

                  TABLE I                                                         ______________________________________                                                                   Minimal                                                                       Effective                                                                     Dose (mg./                                                                    kg. of body                                        Compound                   weight)                                            ______________________________________                                        ethyl 9-oxo-13-trans-prostenoate                                                                         0.5                                                ethyl 20-butyl-9-oxo-13-trans-prostenoate                                                                10                                                 ethyl 20-chloro-9-oxo-13-trans-pros-                                          tenoate                    0.5                                                ethyl 9-oxo-20-nor-13-trans-prostenoate                                                                  0.6                                                ethyl 20-methyl-9-oxo-13-trans-prostenoate                                                               0.5                                                ethyl 17-methyl-9-oxo-19,20-dinor-13-                                         trans-prostenoate          10                                                 ethyl 20-chloro-9-oxo-17,18,19-trinor-                                        13-trans-prostenoate       0.2-1                                              ethyl 9-oxo-13-trans-17-cis-prostadienoate                                                               0.2-2                                              ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-                                      prostenoate                8                                                  ethyl 9-oxo-10a-homo-13-trans-prostenoate                                                                2                                                  ethyl 9-oxo-18-thia-13-trans-prostenoate                                                                 2                                                  ethyl 9-oxo-18-oxythia-13-trans-prosteno-                                     ate                        2                                                  ethyl 20,20-dicarbethoxy-9-oxo-18,19-                                         dinor-13-trans-prostenoate 8                                                  9-oxo-13-trans-prostenoic acid                                                                           0.4                                                9-oxo-6,7-dinor-13-trans-prostenoic acid                                                                 2                                                  20-chloro-9-oxo-13-trans-prostenoic acid                                                                 0.5                                                9-oxo-20-nor-13-trans-prostenoic acid                                                                    0.5-1                                              20-methyl-9-oxo-13-trans-prostenoic acid                                                                 0.5-2                                              17-methyl-9-oxo-19,20-dinor-13-trans-                                         prostenoic acid            0.5                                                20-chloro-9-oxo-17,18,19-trinor-13-trans-                                     prostenoic acid            2-8                                                9-oxo-13-trans-17-cis-prostadienoic acid                                                                 0.2                                                9-oxo-3,4,5,6,7-pentanor-13-trans-prosten-                                    oic acid                   2                                                  9-oxo-10a-homo-13-trans-prostenoic acid                                                                  0.2                                                9-oxo-18-thia-13-trans-prostenoic acid                                                                   0.2                                                9-oxo-18-oxythia-13-trans-prostenoic acid                                                                2-8                                                20-chloro-9-hydroxy-17,18,19-trinor-13-                                       trans-prostenoic acid      2                                                  17-methyl-9-hydroxy-19,20-dinor-13-trans-                                     prostenoic acid            0.2-2                                              9-hydroxy-6,7-dinor-13-trans-prostenoic                                       acid                       2                                                  20-carboxy-9-oxo-18,19-dinor-13-trans-                                        prostenoic acid            8                                                  18-oxa-9-oxo-13-trans-prostenoic acid                                                                    2                                                  3-pyridyl 9-oxo-13-trans-prostenoate                                                                     0.4-4                                              n-butyl 9-oxo-13-trans-prostenoate                                                                       2                                                  β-dimethylaminoethyl 9-oxo-13-trans-                                     prostenoate                0.5-2                                              9-hydroxy-13-trans-prostenoic acid                                                                       2                                                  ______________________________________                                    

This hypotensive effect is short acting and a continuous infusion ofcompound is necessary to maintain the effect. Nevertheless, it isauthoritatively claimed that hypotension induced by prostaglandins is ofan ideal nature and therefore, despite the necessity of infusion, thesecompounds may be useful in the treatment of certain hypertensive crisissituations such as eclampsia. A description of this problem appears inThe Medical Letter on Drugs and Therapeutics (p. 31-32, issue of Apr. 3,1970). Also, in a news item from Medical World News, 10, 12 (Aug. 1,1969), Dr. J. B. Lee, associate professor of medicine at St. LouisUniversity, is quoted as saying that the related prostaglandin Acompounds "might be useful in a hypertensive crisis such as eclampsia."The natural prostaglandins are only difficultly available, and at greatcost. Thus, although the prostaglandin congeners and derivatives may beless potent and larger doses would probably be necessary, the greateravailability of these compounds should provide a substantial economicadvantage.

The prostaglandin-like compounds are also useful as antimicrobialagents. They possess antibacterial and antifungal activity in vitroagainst a variety of standard laboratory microorganisms as determined bythe agar-dilution streak-plate technique. In this assay, the compoundsto be tested are made up to contain 2.5 mg. of test compound permilliliter of solution. Observing sterile techniques, two-fold serialdilutions are made of each test solution. One milliliter of each of theoriginal solutions and of each of the serial dilutions is then added to9 ml. of warm sterile nutrient agar capable of supporting growth of thebacterial test cultures. A second set of agar dilutions is preparedidentical to the first except that the nutrient agar is designed tosupport the growth of the fungal test cultures. The standard sterilenutrient agar solutions containing the different dilutions of the testcompounds, along with suitable and comparable control dilutionscontaining no test compound, are then allowed to cool in Petri dishesthereby forming solidified agar plates. The test bacteria and yeast-likefungi are prepared for use by growing in broth overnight. The spores ofthe filamentous fungi are harvested from mature agar slant cultures andare suspended in sterile physiological saline solution. A loopful ofeach of the resulting live suspensions is then, still employing steriletechniques, streaked upon the surfaces of each of the agar plates andthe resulting streaked plates are then incubated. After an appropriateperiod of time, each of the streaks on each of the plates is inspectedvisually and the extent, if any, of bacterial or fungal growth is noted.The minimal inhibitory concentration (expressed in micrograms permilliliter) is defined as the concentration of test compound causingcomplete inhibition of growth of any particular organism.

In a representative operation, and merely by way of illustration, theminimal inhibitory concentration of typical compounds against a varietyof test organisms as determined in the above-described assay are setforth in Tables II and III below:

                  TABLE II                                                        ______________________________________                                                          Minimal inhibitory                                                            conc. (meg./ml.)                                            Compound            (1)    (2)    (3)  (4)                                    ______________________________________                                        9-oxo-13-trans-prostenoic acid                                                                    50     50     50   50                                     9-oxo-18,19,20-trinor-13-trans-                                               prostenoic acid            250    250  250                                    ethyl 9-oxo-18,19,20-trinor-13-                                               trans-prostenoate                      250                                    ethyl 15-methyl-9-oxo-17,18,19-                                               20-tetranor-13-trans-prostenoate                                                                  250    250    250  250                                    20-butyl-9-oxo-13-trans-prostenoic                                            acid                              250                                         ethyl 20-butyl-9-oxo-13-trans-                                                prostenoate                       250                                         20-chloro-9-oxo-13-trans-                                                     prostenoic acid     250    62     16   62                                     ethyl 20-chloro-9-oxo-13-trans-                                               prostenoate                       250  250                                    9-oxo-20-nor-13-trans-prostenoic                                              acid                50     50     25   25                                     20-methyl-9-oxo-13-trans-                                                     prostenoic acid     100    50     25   25                                     17-methyl-9-oxo-19,20-dinor-13-                                               trans-prostenoic acid                                                                             50     50     25   25                                     9-oxo-10a-homo-13-trans-prostenoic                                            acid                              100  100                                    ethyl 20-chloro-9-oxo-17,18,19-                                               trinor-13-trans-prostenoate            250                                    20-chloro-9-oxo-17,18,19-trinor-                                              13-trans-prostenoic acid                                                                          250    250    250  250                                    9-oxo-6,7-dinor-13-trans-prosten-                                             oic acid            250    250    250  250                                    9-hydroxy-13-trans-prostenoic                                                 acid                50     25     50   50                                     β-dimethylaminoethyl 9-oxo-13-                                           trans-prostenoate   250           250                                         ethyl 20-iodo-9-oxo-17,18,19-                                                 trinor-13-trans-prostenoate       250  250                                    9-oxo-18-thia-13-trans-prosteno-                                              ic acid                    250    125  125                                    ethyl 9-oxo-18-oxythia-13-trans-                                              prostenoate                       250  250                                    9-hydroxy-6,7-dinor-13-trans-                                                 prostenoic acid     250    62     62   62                                     18-oxa-9-oxo-13-trans-pros-                                                   tenoic acid                       250  250                                    9-oxo-13-trans-17-cis-prosta-                                                 dienoic acid        125    62     62   62                                     20-chloro-9-hydroxy-17,18,19-                                                 trinor-13-trans-prostenoic                                                    acid                       250    250  250                                    17-methyl-9-hydroxy-19,20-di-                                                 nor-13-trans-prostenoic acid                                                                             62     62   62                                     ethyl 9-oxo-3,4,5,6,7-pentanor-                                               13-trans-prostenoate              250  125                                    20-mercapto-9-oxo-13-trans-                                                   prostenoic acid            125    250  250                                    9-oxo-3,4,5,6,7-pentanor-13-                                                  trans-prostenoic acid                                                                             250    250    125  250                                    ______________________________________                                         (1) Microsporum canis ATCC 10214                                              (2) Microsporum gypseum ATCC 14683                                            (3) Trichophyton tonsurans NIH 662                                            (4) Trichophyton mentagrophytes E 11                                     

                  TABLE III                                                       ______________________________________                                                          Minimal inhibitory                                                            conc. (meg./ml.)                                            Compound            (5)    (6)    (7)  (8)                                    ______________________________________                                        9-oxo-13-trans-prostenoic acid                                                                    250    62     250  62                                     9-oxo-18,19,20-trinor-13-trans-                                               prostenoic acid                        250                                    ethyl 9-oxo-18,19,20-trinor-13-                                               trans-prostenoate          250                                                ethyl 15-methyl-9-oxo-17,18,19-                                               20-tetranor-13-trans-prosteno-                                                ate                 250    62                                                 20-butyl-9-oxo-13-trans-pros-                                                 tenoic acid                10          10                                     ethyl 20-butyl-9-oxo-13-trans-                                                prostenoate                250                                                20-chloro-9-oxo-13-trans-pros-                                                tenoic acid         62     250    250  62                                     ethyl 20-chloro-9-oxo-13-trans-                                               prostenoate         250    250                                                ethyl 9-oxo-20-nor-13-trans-                                                  prostenoate                62                                                 9-oxo-20-nor-13-trans-prosten-                                                oic acid            50     62     250  62                                     20-methyl-9-oxo-13-trans-pros-                                                tenoic acid         100    25     50   10                                     ethyl 17-methyl-9-oxo-19,20-                                                  dinor-13-trans-prostenoate 62                                                 17-methyl-9-oxo-19,20-dinor-                                                  13-trans-prostenoic acid                                                                          50     62     250  62                                     9-oxo-10a-homo-13-trans-                                                      prostenoic acid            25     100  10                                     ethyl 20-chloro-9-oxo-17,18,-                                                 19-trinor-13-trans-prostenoate                                                                           250                                                20-chloro-9-oxo-17,18,19-tri-                                                 nor-13-trans-prostenoic acid                                                                      250                                                       3-pyridyl 9-oxo-13-trans-                                                     prostenoate                50                                                 ethyl 9-oxo-18-thia-13-trans-                                                 prostenoate                250                                                n-butyl 9-oxo-13-trans-prosten-                                               oate                       250         250                                    ethyl 9-oxo-6,7-dinor-13-trans-                                               prostenoate                250                                                9-oxo-6,7-dinor-13-trans-prosten-                                             oic acid            250    250    250  250                                    9-hydroxy-13-trans-prostenoic                                                 acid                       25     50   25                                     β-dimethylaminoethyl 9-oxo-13-                                           trans-prostenoate          10     50   10                                     ethyl 9-hydroxy-13-trans-prosten-                                             oate                       25                                                 ethyl 20-iodo-9-oxo-17,18,19-tri-                                             nor-13-trans-prostenoate   62                                                 ethyl 20-iodo-9-oxo-13-trans-                                                 prostenoate                62                                                 9-oxo-18-thia-13-trans-prostenoic                                             acid                       250                                                ethyl 20,20-dicarbethoxy-9-oxo-                                               18,19-dinor-13-trans-                                                         prostenoate                250                                                ethyl 9-oxo-18-oxythia-13-trans-                                              prostenoate         250    250                                                ethyl 9-hydroxy-6,7-dinor-13-                                                 trans-prostenoate          6           13                                     9-hydroxy-6,7-dinor-13-trans-                                                 prostenoic acid     250    62     250  62                                     9-oxo-13-trans-17-cis-prosta-                                                 dienoic acid        125    62     250  62                                     20-chloro-9-hydroxy-17,18,19-                                                 trinor-13-trans-prostenoic                                                    acid                                   62                                     17-methyl-9-hydroxy-19,20-di-                                                 nor-13-trans-prostenoic acid                                                                      250    62     125  25                                     ethyl 9-oxo-3,4,5,6,7-pentanor-                                               13-trans-prostenoate       125         125                                    20-mercapto-9-oxo-13-                                                         trans-prostenoic acid      125         6                                      9-oxo-3,4,5,6,7-penta-                                                        nor-13-trans-prostenoic                                                                           250                                                       acid                                                                          ______________________________________                                         (5) Trichophyton rubrum E 97                                                  (6) Mycobacterium smegmatis ATCC 606                                          (7) Staphylococcus aureus Rose ATCC 14154                                     (8) Streptococcus pyogenes C 203                                         

All of the compounds of this invention can be isolated and purified byconventional methods. Isolation can be accomplished, for example, bydilution of the reaction mixture with water, extraction with awater-immiscible solvent such as methylene chloride, ethyl acetate,benzene, cyclohexane, ether, toluene and the like, chromatography,adsorption on ion-exchange resins, distillation, or a combination ofthese. Purification of the compounds of this invention can beaccomplished by means known in the art.

The novel compounds of the present invention are obtainable as yellowoils as solids having characteristic absorption spectra. They arerelatively soluble in common organic solvents such as ethanol, ethylacetate dimethylformamide, and the like.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation of2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)cyclopentan-1-one

To a stirred solution of the sodium cyclopentanone carboxylate enolatein dimethoxyethane, prepared from 187 g. (1.248 moles) of2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g.(1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. ofdimethoxyethane, is added dropwise 309 g. (1.212 miles) of ethyl5-iodovalerate. The reaction mixture is stirred and heated at reflux for18 hours. The mixture is cooled and filtered. The solvent is removedfrom the filtrate by evaporation and the residue is poured into dilutehydrochloric acid and extracted with ether. The combined extracts arewashed with water and saline, dried over magnesium sulfate andevaporated to give an oil. The oil is distilled under reduced pressureto give 274 g. of a light yellow oil, b.p. 140°-143° C. (0.17 mm).

EXAMPLE 2 Preparation of 2-(4-carboxybutyl)cyclopentan-1-one

A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethylesters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for20 hours. Solution occurs in approximately one-half hour. The solutionis cooled and diluted with water and extracted with ether. The combinedextracts are washed with saline and dried over magnesium sulfate andevaporated. The residue is evaporated twice with toluene to give 144 g.of an oil.

EXAMPLE 3 Preparation of 2-(4-carbethoxybutyl)cyclopentan-1-one

A stirred solution of 124 g. (0.673 mole) of2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18hours. The solvent is evaporated and the residue is dissolved in ether.The ether solution is washed with saline, dilute sodium bicarbonatesolution and again with saline, dried over magnesium sulfate andevaporated. The oil is distilled under reduced pressure to give 149 g.of a colorless oil, b.p. 106°-109° C. (0.23 mm).

EXAMPLE 4 Preparation of2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 1, treatment of 2-cyclopentanonecarboxylate (mixed methyl and ethyl esters) with sodium hydride indimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil,b.p. 136°-137° C. (0.16 mm).

EXAMPLE 5 Preparation of 2-(3-carboxypropyl)cyclopentan-1-one

In the manner described in Example 2, treatment of 2-carbalkoxy(mixedmethyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one(Example 4) with a 20% hydrochloric acid and acetic acid mixture gives ayellow oil.

EXAMPLE 6 Preparation of 2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 3, treatment of2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonicacid monohydrate in ethanol gives a colorless oil, b.p. 93° C. (0.10mm).

EXAMPLE 7 Preparation of ethyl and methyl2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate

In the manner described in Example 1, ethyl and methyl 2-cyclopentanonecarboxylate is reacted with ethyl 7-bromoheptanoate to furnish thesubject product, b.p. 147° C. (0.09 mm).

EXAMPLE 8 Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one

In the manner described in Example 2, ethyl and methyl2-(6-carbethoxyhexyl)-1-cyclopentanone-2-carboxylate (Example 7) ishydrolyzed to furnish the subject product, b.p. 143° C. (0.05 mm).

EXAMPLE 9 Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one

In the manner described in Example 3,2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnishthe subject product, b.p. 110° C. (0.03 mm).

EXAMPLE 10 Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene

A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one(Example 9) in 250 ml. of acetic anhydride containing 0.940 g. ofp-toluenesulfonic acid monohydrate is heated to boiling under partialreflux allowing distillate at 118° C. or less (i.e., acetic acid) toescape through a Vigreaux column equipped with a condenser to collectthe distillate. After 16 hours, during which period acetic anhydride isadded in portions in order to keep the solvent level at at least 100ml., the solution is cooled and poured cautiously into a stirred coldmixture of saturated sodium bicarbonate solution (400 ml.) and hexane(250 ml.). The resulting mixture is stirred for an additional 30 minutesduring which period solid sodium bicarbonate is added periodically toinsure a basic solution. The hexane layer is separated and washed withsaturated sodium chloride solution, dried with anhydrous magnesiumsulfate and taken to dryness. Distillation of the residual oil gives 102g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm.).

EXAMPLE 11 Preparation of1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene

In the manner described in Example 10, treatment of2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with aceticanhydride and p-toluenesulfonic acid monohydrate gives a yellow oil,b.p. 98°-103° C. (0.35 mm).

EXAMPLE 12 Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene

In the manner described in Example 10, treatment of2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydrideand p-toluenesulfonic acid monohydrate gives a yellow oil, b.p.109°-110° C. (0.37 mm).

EXAMPLE 13 Preparation of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of 50 g. of1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 10) in 150 ml.of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooledin an ice bath, is added dropwise over a period of about 30 minutes, asolution of 30 g. of bromine in 50 ml. of carbon tetrachloride. Afterstirring for an additional 45 minutes the chloroform layer is separatedand washed successively with dilute sodium thiosulfate solution,saturated sodium chloride solution, dried with anhydrous magnesiumsulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,N-dimethylformamide andadded to a mixture of 33 g. of lithium bromide and 32 g. of lithiumcarbonate in 375 ml. of N,N-dimethylformamide, previously dried byrefluxing with 375 ml. of benzene under a Dean-Stark apparatus followedby distillation of the benzene. The mixture is stirred at the refluxtemperature for 30 minutes, then cooled and poured into 850 ml. ofice-cold water. The resulting mixture is acidified (cautiously) with 4Nhydrochloric acid and extracted with ether three times. The combinedether extracts are washed with saturated sodium chloride solution, driedwith anhydrous magnesium sulfate and taken to dryness under reducedpressure to afford 41.5 g. of an amber oil. In order to convert anyisomeric material to the desired product, 41.5 g. of the above materialis treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450ml. of absolute alcohol at the reflux temperature for 18 hours. Thesolution is taken to dryness under reduced pressure. The resulting gumis dissolved in ether and washed with saturated sodium bicarbonatesolution, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate and taken to dryness under reduced pressure. Theresidual oil is distilled to give 30.2 g. of product; b.p. 118° C. (0.05mm.); λ_(max) ^(MeOH) 229 mμ (ε9950); λ_(max) 5.75, 5.85, 6.15, 8.45 μ;phase chromatography shows 99% product, containing 1%2-(6-carbethoxyhexyl)cyclopentan-1-one.

This product can be purified by the following procedure. A mixture of120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containingapproximately 5% of the saturated analogue, and 7.67 g. (10 molepercent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol isstirred at ambient temperatures for 18 hours and is then refluxed for 1hour. The mixture is cooled, the solvent is evaporated, and the residueis taken up into 150 ml. of chloroform and passed through a column of450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield acolorless oil containing <0.5% of the saturated impurity.

EXAMPLE 14 Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one

In the manner described in Example 13, bromination of1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 11) followed bydehydrobromination with lithium bromide and lithium carbonate isproductive of the subject compound.

EXAMPLE 15 Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one

In the manner described in Example 13, treatment of1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 12) with bromineand subsequent treatment of the brominated product with a mixture oflithium bromide and lithium carbonate in N,N-dimethylformamide isproductive of the subject compound. Treatment of this product withp-carboxyphenylhydrazine by the procedure of Example 13 furnishes aproduct which contains less than 0.5% of the corresponding saturatedketone.

EXAMPLE 16 Preparation of1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene

To a mixture of 35.97 g. (0.151 mole) of2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) and 15.0 g. (0.180mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol isadded 25 ml. of pyridine and the resulting solution is stirred for 20hours at ambient temperatures. The solvent is evaporated and the residueis partitioned between water and diethyl ether. The organic phase iswashed with water and saturated brine, dried (Na₂ SO₄), and the solventis evaported to yield an oil. Distillation yields 38.7 g. of a colorlessoil, b.p. 115°-118° C. (0.075 mm). IR (film): 1740, 1627, 1053, 890cm⁻¹. λ_(max) (MeOH) 243 (13,000). NMR δ (CDCl₃): 3.89.

EXAMPLE 17 Preparation of1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene

To an ice cooled solution of 34.10 g. (0.128 mole) of1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200ml. of benzene under nitrogen is added dropwise 225 ml. of a 25%solution of diisobutyl aluminum hydride in hexane. The resultingsolution is stirred for 2 hours at 0°-5° C., poured onto ice and dilutehydrochloric acid, and the aqueous phase is saturated with sodiumchloride. The organic phase is separated, washed with saturated brine,dried (Na₂ SO₄), and evaporated to yield an oil. The latter is dissolvedin 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p.62°-64° C. IR (KBr) 3260, 1630, 1059, 893 cm⁻¹ λ_(max) 243 (14,200). NMR(CDCl₃) δ: 2.37.

EXAMPLE 18 Preparation of1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene

To a solution of 5.00 g. (0.0222 mole) of1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 17) in 50 ml.of dry pyridine at 0° C. is added 8.45 g. (0.0444 mole) ofp-toluenesulfonyl chloride and the resulting solution is chilled at 5°C. overnight. The mixture is partitioned between 300 ml. of ice waterand diethyl ether. The organic phase is washed with 1:1 ice coldhydrochloric acid, cold water, and cold saturated brine, dried (NaSO₄/K₂ CO₃), and evaporated under reduced pressure at room temperature toyield an oil. The latter is dissolved in 600 ml. of hexane, treated with0.5 g. of Darco, filtered and evaporated to yield 7.7 g. of a colorlessoil. IR (film) 1600, 1192, 1182, 1053, 890 cm⁻¹. λ_(max) (MeOH) 228 and243.

EXAMPLE 19 Preparation of1-methoximino-2-(8,8-dicarbethoxyoctyl)-2-cyclopentene

To an alcoholic solution of diethyl sodio malonate, prepared from 0.847g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g.(0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate ofExample 18 and the mixture is refluxed for 2 hours under a nitrogenatmosphere. The mixture is partitioned between cold dilute hydrochloricacid and diethyl ether, and the organic phase is washed with water andsaturated brine, dried (Na₂ SO₄), and evaporated to yield an oil. Theexcess diethyl malonate is distilled off under reduced pressure to yield6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm⁻¹.

EXAMPLE 20 Preparation of1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopentene

A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. ofpotassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1hour, cooled, and is partitioned between water and diethyl ether. Theaqueous phase is acidified with hydrochloric acid, extracted with ether,and the organic phase is washed with water and saturated brine, dried(Na₂ SO₄) and evaporated to yield a solid. The solid is crystallizedfrom benzene to yield 4.15 g. of tan crystals, m.p. 135°-137° C. (-CO₂).

EXAMPLE 21 Preparation of1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene

A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20ml. of xylene is refluxed for 1.5 hours, cooled, and evaporated to yielda tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm⁻¹.

EXAMPLE 22 Preparation of 2-(8-carboxyoctyl)cyclopent-2-en-1-one

The acid methoxime from Example 21 is refluxed for 5 hours with 55 ml.of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled,the solvent is evaporated, and the residue is partitioned between waterand diethyl ether. The organic phase is washed with water and saturatedbrine, dried (Na₂ SO₄), and evaporated to yield a tan solid. IR (KBr)1745, 1665 cm⁻¹. λ_(max) (MeOH) 228 (12,600).

EXAMPLE 23 Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one

The acid ketone from Example 22 is Fisher esterified with 100 ml. ofabsolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonicacid for 6 hours, cooled, and the solvent is evaporated. The resultingoil is dissolved in 3:1 benzene-ether and the solution is passed througha column of 100 g. of Florisil® . The filtrate is evaporated and theresidue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139°C. (0.05 Torr).

EXAMPLE 24 Preparation of 2-(4-carbethoxybutyl)-2-cyclopentenonemethoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) withmethoxyamine hydrochloride in the manner described in Example 16 givesan oil, b.p. 107°-109° C. (0.05 mm). IR (film): 1740, 1628, 1050, 885cm⁻¹. λ_(max) (MeOH) 243 (13,600).

EXAMPLE 25 Preparation of 2-(5-(hydroxypentyl)-2-cyclopentenonemethoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone as methoxime(Example 24) with diisobutyl aluminum hydride in the manner described inExample 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050,886 cm⁻¹. λ_(max) ^(MeOH) 243 (12,020).

EXAMPLE 26 Preparation of2-(5-p-toluenesulfonyloxypentyl)-2-cyclopentenone methoxime

Treatment of 2-(hydroxypentyl)-2-cyclopentenone methoxime (Example 25)with p-toluenesulfonyl chloride in pyridine in the manner described inExample 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885cm⁻¹.

EXAMPLE 27 Preparation of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenonemethoxime

To a solution of diethyl sodio ethylmalonate, prepared from 1.63 g.(0.0387 mole) of sodium hydride in mineral oil (57.2%) and 8.5 g.(0.0452 mole) of diethyl ethylmalonate in 100 ml. of ethylene glycoldimethyl ether, is added 7.5 g. of tosylate from Example 26 in 20 ml. ofethylene glycol dimethyl ether and the mixture is refluxed for 3 hoursand then allowed to stand at room temperature for 18 hours undernitrogen atmosphere. The reaction mixture is filtered and most of thesolvent is removed. The mixture is partitioned between cold dilutehydrochloric acid and diethyl ether, and the organic phase is washedwith water and saturated brine, dried (MgSO₄), and evaporated to yieldan oil. The excess diethyl ethylmalonate is distilled off under reducedpressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627,1050, 885 cm⁻¹.

EXAMPLE 28 Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenonemethoxime

Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenone methoxime(Example 27) with potassium hydroxide, and 1:1 aqueous methanol in themanner described in Example 20 gives a light yellow oil.

EXAMPLE 29 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime

In the manner described in Example 21, treatment of2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) withxylene at reflux for 18 hours gives a yellow oil.

EXAMPLE 30 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime (Example 29)with acetone and 2N hydrochloric acid in the manner described in Example22 gives a light yellow oil.

EXAMPLE 31 Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 30) withthionyl chloride and then treatment of the acid chloride with ethanolgives an amber oil. The oil is placed on a magnesia-silica gel columnand eluted with 3:1 benzene:ether. The solvent is removed and theresidue is distilled, b.p. 122° C. (0.06 mm).

EXAMPLE 32 Preparation of2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example16, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) and methoxyaminehydrochloride.

EXAMPLE 33 Preparation of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example17, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene anddiisobutylaluminum hydride.

EXAMPLE 34 Preparation of2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene

To an ice cold solution of 4.833 g. (0.0266 mole) of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene in 50 ml. of drytetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyllithium in hexane, dropwise. The reaction mixture is stirred for 0.5hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is addeddropwise. The reaction mixture is stirred overnight at room temperatureand then refluxed for 1.5 hours. The reaction is cooled and poured intowater and extracted several times with ether. The ether extracts arewashed with saline, dried over magnesium sulfate, and concentrated. Theresidue is placed on an alumina column, chloroform being used as a washsolvent. The combined washings are concentrated to dryness to give 4.903g. of product as a yellow oil.

EXAMPLE 35 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetoneand 2N hydrochloric acid at reflux gives the subject compound as ayellow oil.

EXAMPLE 36 Preparation of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 23, treatment of2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid inethanol produces the subject product as a light yellow oil

EXAMPLE 37 Preparation of2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene

In the manner described in Example 18, treatment of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene with p-toluene sulfonylchloride in pyridine gives the subject product as a light yellow oil; IR(film): 1600, 1190, 1050, 885 cm⁻¹.

EXAMPLE 38 Preparation of2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentane

To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2%in mineral oil) in 50 ml. of dimethoxyethane, under nitrogen, is addedslowly 4.8 g. (0.0347 mole) of ethyl 2-mercaptoacetate. The reactionmixture is stirred at room temperature for one hour and then a solutionof 7.8 g. (0.0231 mole) of2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml.of dimethoxyethane is added dropwise and stirred at room temperature for18 hours. The solution is heated at reflux for one hour, cooled andpoured into cold dilute hydrochloric acid and then extracted with ether.The combined ether extracts are washed with saline, dried over magnesiumsulfate and evaporated to give 7.6 g. of subject product as a yellowoil.

EXAMPLE 39 Preparation of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetoneand 2N hydrochloric acid at reflux gives the subject product as a yellowoil.

EXAMPLE 40 Preparation of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 23, treatment of2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acidin ethanol gives the subject ester as a yellow oil.

EXAMPLE 41 Preparation of2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene

To an ice cold solution of 3.66 g. (0.02 mole) of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentane (Example 33) in 50 ml.of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 Mn-butyl lithium in hexane. The reaction mixture is stirred for half anhour and then the lithium salt of chloroacetic acid, prepared from 1.89g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6 M n-butyl lithiumin 20 ml. of dimethoxyethane, is added and the reaction mixture isheated at reflux for 48 hours. The solvent is evaporated and the residueis partitioned between ether and water. The aqueous phase is acidifiedwith hydrochloric acid and extracted with ether. The organic phase iswashed with water and saturated saline solution, dried (MgSO₄), andevaporated to give 3.35 g. of a yellow oil.

EXAMPLE 42 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopenten-1-one

In the manner described in (Example 22), treatment of2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 42) withacetone and 2N hydrochloric acid at reflux gives the subject compound asa yellow oil.

EXAMPLE 43 Preparation of1-methoximino-2-(4-methanesulfonyloxybutyl)-2-cyclopentene

To a solution of 1.83 g. (0.01 mole) of1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 33) in 10 ml.of methylene chloride containing 1.52 g. (0.015 mole) of triethylamineis added 1.265 g. (0.011 mole) of methanesulfonyl chloride over a periodof 5-10 minutes at -10°-0° C. Stirring is continued for 15 minutes andthe solution is then washed with cold water, cold 10% hydrochloric acid,cold sodium bicarbonate solution, and cold saline solution. The organicphase is dried (MgSO₄) and concentrated to give an oil which solidifiesupon cooling. Crystallization from ether-petroleum ether (30°-60° C.)gives 1.797 g. of white crystals, m.p. 67°-68° C.

EXAMPLE 44 Preparation of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene

A mixture of 2.75 g. (0.01 mole) of1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentane (Example 54)and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dryN,N-dimethylformamide is heated at 65°-70° C. for 3 hours. The cooledreaction mixture is poured into water and extracted with diethyl ether.The organic phase is washed with water and saturated saline solution,dried (MgSO₄), and evaporated to give 1.89 g. of a light yellow oil.

EXAMPLE 45 Preparation of1-methoximino-2-(5-carboxypentyl)-2-cyclopentene

A mixture of 1.89 g. (0.0092 mole) of1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 44) and 1 g.(0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol isrefluxed for 48 hours, cooled, and partitioned between water and diethylether. The aqueous phase is acidified with hydrochloric acid, extractedwith diethyl ether, and the organic phase is washed with water andsaturated saline solution, dried (MgSO₄), and evaporated to give 1.86 g.of a yellow oil.

EXAMPLE 46 Preparation of 2-(5-carboxypentyl)-2-cyclopentenone

A solution of 1.86 g. (0.00825 mole)1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 45) in 44 ml.of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours.The solvent is partially evaporated and a solid precipitates and iscollected. The residue is extracted with diethyl ether and the organicphase is washed with saturated saline solution, dried (MgSO₄), andevaporated to yield additional solid. The combined solid material iscrystallized from ether/pet ether (30°-60° C.) to yield crystallinematerial, m.p. 70°-72° C.

EXAMPLE 47 Preparation of 2-(5-carbethoxypentyl)-2-cyclopentenone

A solution of 1.309 g. (0.00668 mole) of2-(5-carboxypentyl)-2-cyclopentenone (Example 46) and 90 mg. ofp-toluene-sulfonic acid in 150 ml. of ethanol is refluxed for 18 hours.The solvent is evaporated and the residue is dissolved in ether. Theorganic phase is washed with water, sodium bicarbonate solution, andsaturated saline solution, dried (MgSO₄), and evaporated to give 1.371g. of a light yellow oil.

EXAMPLE 48 Preparation of2-(5-acetoxypentyl)-2-carbomethoxy/carbethoxy-cyclopentanone

A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200g. (8.3 moles) of mineral oil free sodium hydride in 10 l. of1,2-dimethoxyethane, 1320 g. (8.0 moles) of 5-chloro-1-amyl acetate [M.E. Synerholm, Journ. Amer. Chem. Soc., 69, 2681 (1947)], and 1200 g.(8.0 moles) of sodium iodide is refluxed under nitrogen for 18 hours.The mixture is cooled, concentrated to 4 l., and partitioned betweendilute hydrochloric acid and diethyl ether. The organic phase is washedwith water and saturated brine, dried (MgSO₄), and evaporated to yield1920 g. of an oil.

EXAMPLE 49 Preparation of2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxy-pentyl)-cyclopentanone

A mixture of 4,500 g. (16.2 moles) of2-acetoxy-pentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example48), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloricacid, and 1 l. of water is refluxed for 18 hours, cooled, andpartitioned between saturated brine and benzene. The organic phase iswashed with saturated brine, dried (MgSO₄), and evaporated in vacuo toyield 3155 g. of an oil.

EXAMPLE 50 Preparation of 1-acetoxy-2-(5-acetoxypentyl)-1-cyclopentene

A solution of 400 g. (2.04 moles) of a mixture of2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone(Example 49) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. ofacetic anhydride is refluxed at a rate to maintain a steady distillationof acetic acid from the reaction through a helice-packed fractionationcolumn. The reaction is continued with the addition of acetic anhydrideto maintain a constant volume until complete conversion of startingmaterials to product is evident. The mixture is cooled and partitionedbetween 2 l. of hexane and 3 l. of cold water containing solid sodiumbicarbonate to maintain a neutral pH. The organic phase is washed withsaturated brine, dried (MgSO₄), and evaporated to yield 452 g. of anoil.

EXAMPLE 51 Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone

To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3l. of water, and 2.5 l. of chloroform cooled to 5° C. is addedsimultaneously 1016 g. (4.0 moles) of1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 50) and asolution of 648 g. (4.05 moles) of bromine in 500 ml. of carbontetrachloride at a rate to maintain a temperature below 10° C. Themixture is stirred for half an hour after addition of the reagents andthe phases are then separated. The organic phase is washed with 2%sodium thiosulfate solution, water, and saturated brine, dried (MgSO₄),and evaporated in vacuo to an oil. The oil is immediately added to arefluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l. ofN,N-dimethylacetamide under nitrogen and the mixture is then refluxedfor thirty minutes. The mixture is cooled, filtered and partitionedbetween water and diethyl ether. The organic phase is washed with waterand saturated brine, dried (MgSO₄), and evaporated to yield 757 g. of anoil, b.p. 116°-118° C. (0.25 mm.).

EXAMPLE 52 Preparation of1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene

In the manner described for Example 16,2-(5-acetoxypentyl)-2-cyclopentenone (Example 51) is treated withmethoxyamine hydrochloride in pyridine and ethanol to yield the subjectcompound, b.p. 101°-103° C. (0.20 mm.).

EXAMPLE 53 Preparation of1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene

A mixture of 74 g. (0.22 mole) of1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 52) and 56 g.(1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol isrefluxed for 2 hours and then cooled. The solvent is partially removedin vacuo and the residue is partitioned between saturated brine anddiethyl ether. The organic phase is washed with saturated brine, dried(MgSO₄), and evaporated to yield an oil which crystallized, m.p. 35°-36°C.

EXAMPLE 54 Preparation of1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene

To a cold solution of 9.85 g. (0.05 mole) of1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 53) and 7.6 g.(0.075 mole) of triethylamine in 100 ml. of methylene chloride at a rateto maintain a temperature of -10° to 0° C. The mixture is then stirredfor 15 minutes and then poured into ice water. The organic phase iswashed with cold 10% hydrochloric acid, cold saturated sodiumbicarbonate solution, and cold saturated brine, dried (MgSO₄), andevaporated to yield a solid, m.p. 78°-80° C.

EXAMPLE 55 Preparation of1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene

To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, preparedfrom 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) ofmineral oil free sodium hydride in 1 l. of 1,2-dimethoxyethane undernitrogen, is added 170 g. (0.62 mole) of 1methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 54;in 1.5 l. of 1,2-dimethoxyethane and the mixture is refluxed for 5hours. The mixture is cooled, filtered, and the solvent is evaporated.The residue is partitioned between cold dilute hydrochloric acid andwater, and the organic phase is washed with saturated brine, dried(MgSO₄), evaporated to remove solvent and excess diethyl malonate toyield 209 g. of an oil.

EXAMPLE 56 Preparation of1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene

In the manner described in Example 20,1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated withpotassium hydroxide in 1:1 aqueous methanol and the hydrochloric acid toyield the desired compound as crystals from diethyl ether, m.p.110°-115° C.

EXAMPLE 57 Preparation of1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene

A solution of 141 g. (0.50 mole) of1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. ofbis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, andevaporated to yield an oil. The latter is crystallized from hexane toyield 92 g. of solid, m.p. 70°-72° C.

EXAMPLE 58 Preparation of 2-(6-carboxyhexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene (Example 57) withacetone and 2N hydrochloric acid at reflux provides the subjectcompound.

EXAMPLE 59 Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone

Fischer esterification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example58) in the manner of Example 23 provides the subject compound.

EXAMPLE 60 Preparation of1-methoximino-2-(6-fluoro-6-dicarbethoxyhexyl)-2-cyclopentene

To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g.(0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dryN,N-dimethylformanide and 8.174 g. (0.0458 mole) of diethylfluoromalonate is added dropwise 11.32 g (0.0413 mole) of1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 54)in 60 ml. of N,N-dimethylformanide. The mixture is refluxed for 2 hoursunder a nitrogen atmosphere. The mixture is concentrated and partitionedbetween cold dilute hydrochloric acid and diethyl ether, and the organicphase is washed with saturated brine, dried (MgSO₄), and evaporated toyield 13.631 g. (92%) of a yellow oil.

EXAMPLE 61 Preparation of1-methoximino-2-(6-fluoro,6-dicarboxyhexyl)-2-cyclopentene

A mixture of 13.631 g. of the diester of Example 60 and 16 g. ofpotassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5hours, cooled, concentrated, and is partitioned between water anddiethyl ether. The aqueous phase is acidified with hydrochloric acid,extracted with ether, and the organic phase is washed with saturatedbrine, dried (MgSO₄) and evaporated to yield a solid. The solid iscrystallized from diethyl ether petroleum ether (30°-60° C.) to give 10g. (90%) of white crystals, m.p. 143°-145° C. (-CO.sub. 2).

EXAMPLE 62 Preparation of1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene

A solution of 10 g. of the diacid of Example 61 in 60 ml. of2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated toyield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethylether-petroleum ether (30°-60° C.) to give white crystals, m.p. 98°-100°C.

EXAMPLE 63 Preparation of2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one

The acid methoxime (8.5 g.) from Example 62 is refluxed for 5 hours with180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture iscooled, the solvent is evaporated, and the residue is partitionedbetween water and diethyl ether. The organic phase is washed withsaturated brine, dried (MgSO₄) and evaporated to yield 7.4 g. (98%) of alight yellow oil.

EXAMPLE 64 Preparation of2-(6-fluoro-6-carbethoxyhexyl)cyclopent-2-en-1-one

The acid ketone (7.4 g.) from Example 63 is Fischer esterified with 300ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18hours, cooled, and the solvent is evaporated. The resulting oil isdissolved in ether, washed with dilute sodium bicarbonate solution,saline, dried (MgSO₄) and to give 7.306 g. (86%) of a light yellow oil.

EXAMPLE 65 Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene(Example 18) with sodium cyanide in the manner of Example 44 isproductive of the subject compound.

EXAMPLE 66 Preparation of2-(7-carboxyheptyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene(Example 65) by the procedure of Example 45 is productive of the subjectcompound.

EXAMPLE 67 Preparation of 2-(7-carboxyheptyl)-2-cyclopentene-1-one

Hydrolysis of the methoxime of Example 66 with acetone-hydrochloric acidby the procedure of Example 46 is productive of the subject compound.

EXAMPLE 68 Preparation of 2-(7-carbethoxyheptyl)-2-cyclopenten-1-one

Fisher esterification of the carboxylic acid of Example 67 by theprocedure of Example 47 is productive of the subject compound.

EXAMPLE 69 Preparation of2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene(Example 54) with sodio diethyl phenylmalonate by the procedure ofExample 55 is productive of the subject compound.

EXAMPLE 70 Preparation of2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example69) by the procedure of Example 20 is productive of the subject diacid.

EXAMPLE 71 Preparation of2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Decarboxylation of2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example70) by the procedure of Example 57 is productive of the subjectcompound.

EXAMPLE 72 Preparation of 2-(6-carboxy-6 -phenylhexyl)-2-cyclopentene-1-one

Methoxime cleavage of2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 71) inthe manner of Example 63 is productive of the subject ketone.

EXAMPLE 73 Preparation of2-(6-carbethoxy-6-phenylhexyl)-2-cyclopentene-1-one

Fisher esterification of the carboxylic acid of Example 72 in the mannerof Example 64 is productive of the subject keto-ester.

EXAMPLE 74 Preparation of2-(6-fluoro-6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene

An ethanolic solution of sodium ethoxide, prepared from 0.389 g. ofsodium and 40 ml. of absolute ethanol, is treated at ambienttemperatures with 5.05 g. of2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 55). Theresulting solution is cooled to -20° C. and then treated with a streamof perchloryl fluoride until the mixture becomes neutral. The excessperchloryl fluoride is removed with a stream of nitrogen and the mixtureis retreated with 10 ml. of an ethanolic solution of sodium ethoxide(from 0.350 g. of sodium) and then with perchloryl fluoride until themixture becomes neutral. The excess perchloryl fluoride is removed witha stream of nitrogen and the mixture is filtered and evaporated to anoil. The latter is partitioned between ether and water and the organicphase is washed with saturated saline, dried (Na₂ SO₄) and evaporated toafford the subject compound.

EXAMPLE 75 Preparation of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene

A mixture of 15.24 g. of 2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene (Example 37) and 10.70 g. of sodium bromidein 100 ml. of dimethylsulfoxide is stirred at ambient temperature for 48hours and then poured into 600 ml. of water. The mixture is extractedwith hexane and its organic phase is wasted with saturated brine, dried(NaSO₄), and evaporated to yield a tan oil.

EXAMPLE 76 Preparation of 2-(4-iodobutyl)-1-methoximino-2-cyclopentene

To a solution of 1.5 g. of sodium iodide in 20 ml. of acetone is added2.3 g of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene (Example 75) andthe resulting mixture is stirred at ambient temperatures for 5 hours.The mixture is filtered and evaporated and the residue is partitionedbetween water and benzene. The organic phase is washed with saturatedbrine, dried (NaSO₄), and evaporated to yield a tan oil.

EXAMPLE 77 Preparation of1-methoximino-2-(5-chloropentyl)-2-cyclopentene

A solution of 5 g. (0.0182 mole) of2-(5-methylsulfonyloxypentyl)-2-cyclopentenone methoxime (Example 54)and 5 g. of lithium chloride in 100 ml. of N,N-dimethylformamide isheated at reflux for one hour. The solution is cooled and 100 ml. ofwater is added and extracted with diethyl ether. The combined extractsare washed with saline, dried (MgSO₄), and evaporated to yield a lightyellow oil.

EXAMPLE 78 Preparation of1-methoximino-2-(6,6-dicarbethoxyhexyl)cyclopent-2-ene

Treatment of 1-methoximino-2-(5-chloropentyl)-2-cyclopentene (Example77) with sodio diethylmalonate in the manner of Example 55 is productiveof the subject compound.

EXAMPLE 79 Preparation of1-methoximino-2-(5,5-dicarbethoxypentyl)-2-cyclopentene

Treatment of 2-(4-iodobutyl)-1-methoximino-2-cyclopentene (Example 76)or of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene (Example 75) withsodio diethylmalonate in the manner of Example 55 is productive of thesubject compound.

EXAMPLE 80 Preparation of ethyl 9-oxo-13-trans-prostenoate

A solution of 1.102 g. of 1-octyne in 2 ml. of benzene is treated with11.5 ml. of 15% diisobutylaluminum hydride in toluene and the solutionis heated to 50° C. for 2 hours. The solution is cooled, its solvent isremoved in vacuo, and the resulting oil is treated with 5.45 ml. of5.10% methyl lithium in diethyl ether with ice cooling. To the resultingsolution is added 1.830 g. of 2-(6 -carbethoxyhexyl)-2-cyclopentenone(Example 13) and the solution is stirred at ambient temperatures for 18hours. The solution is poured onto ice and dilute hydrochloric acid, andthe mixture is extracted with diethyl ether. The organic phase is washedwith dilute sodium bicarbonate, water, and saturated brine, dried andevaporated. The residue is purified by chromatography on Florisil® anddistillation to yield 1.878 g. of an oil, 1I 1736 cm⁻ (ester and ketonecarbonyls) 969 cm⁻¹ (trans vinyl group); NMR (CDCl.sub. 3) δ5.14-5.87(multiplet, 2H, vinyl protons, J trans=15 Hz); Mass Spectrum, parentpeak at 350 mμ.

EXAMPLE 81 Preparation of ethyl 20-butyl-9-oxo-13-trans-prostenoate

In the manner described in Example 80,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 1-dodecyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR3740 cm⁻¹ (ester and ketone carbonyls) 967 cm⁻¹ (trans vinyl group).

EXAMPLE 82 Preparation of ethyl-9-oxo-18,19,20-trinor-13-trans-prostenoate

In the manner described in Example 80,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 1-pentyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by distillation to give a liquid, IR 1740 cm⁻¹(ester and ketone carbonyls) 967 cm⁻¹ (trans vinyl group).

EXAMPLE 83 Preparation of ethyl 15-methyl-9-oxo-17,18,19,20-tetranor-13-trans-prostenoate

In the manner described in Example 80,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 3-methyl-1-butyne, diisobutylaluminum hydride, andmethyl lithium. The crude product obtained by acid hydrolysis and etherextraction is purified by distillation to give a liquid, IR 1740 cm⁻¹(ester and ketone carbonyls) 967 cm⁻¹ (trans vinyl group).

EXAMPLE 84 Preparation of ethyl 20-chloro-9-oxo-13-trans-prostenoate

In the manner described in Example 80,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 8-chloro-1-octyne [W. J. Gensler and G. R. Thomas,J. Amer. Chem. Soc., 73, 4601 (1951)], diisobutylaluminum hydride, andmethyl lithium. The crude product obtained by acid hydrolysis ispurified by silica gel chromatography to give an oil, IR 1740 cm⁻¹(ester and ketone carbonyls), 967 cm⁻¹ (trans vinyl group).

EXAMPLE 85 Preparation of ethyl 9-oxo-20-nor-13-trans-prostenoate

A solution of 5.30 g. of 1-heptyne in 10 ml. of benzene is treated with40 ml. of 1.2N diisobutylaluminum hydride in hexane and at 50° C. for 2hours. The solution is cooled in an ice bath and diluted with 25 ml. ofether. To the solution is added 30 ml. of 1.6M n-butyl lithium inhexane. After stirring for 20 minutes at 15°-25° C. the resultingsolution is treated with a solution of2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13). The mixture isstirred at 5°-25° C. for 18-20 hours and the product then is hydrolyzedwith a mixture of ice and hydrochloric acid. The crude product, obtainedfrom the organic phase, is purified by chromatography on silica gel togive an oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) and 967 cm⁻¹(trans vinyl group).

EXAMPLE 86 Preparation of ethyl 20-methyl- 9-oxo-13-trans-prostenoate

In the manner described in Example 85,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 1-nonyne, diisobutyl aluminum hydride and n-butyllithium. The crude product obtained by acid hydrolysis and evaporationof organic solvent is purified by chromatography on silica gel to givean oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) and 967 cm⁻¹ (transvinyl group).

EXAMPLE 87 Preparation of ethyl17-methyl-9-oxo-19,20-dinor-13-trans-prostenoate

In the manner described in Example 85,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 5-methyl-1-hexyne, diisobutylaluminum hydride andn-butyl lithium. The crude product obtained by acid hydrolysis andevaporation of the organic solvent is purified by chromatography onsilica gel to give an oil, IR 1740 cm⁻¹ (ester and ketone carbonyl and967 cm⁻¹ (trans vinyl group).

EXAMPLE 88 Preparation of ethyl 20-chloro-9-oxo-17,18,19-trinor-13-trans-prostenoate

In the manner described in Example 85,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride,and n-butyl lithium. The crude product, obtained by acid hydrolysis andevaporation of the organic solvent, is purified by distillation to givean oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) and 967 cm⁻¹ (transvinyl group).

EXAMPLE 89 Preparation of ethyl 9-oxo-13-propyl-18,19,20-trinor-13-transprostenoate

In the manner described in Example 85,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from 4-octyne, diisobutylaluminum hydride, and n-butyllithium. The crude product mixture, obtained by acid hydrolysis andevaporation of the organic solvent, is separated by chromatography onsilica gel and distillation to give ethyl 9-oxo-13-propyl-18,19,20-trinor-13-trans-prostenoate as an oil, IR 1740 cm⁻¹ (ester and ketonecarbonyls); NMR (CCl₄) δ 5.2 ppm (multiplet, vinyl proton) and a secondoil (ethyl 9-oxo-17,18,19,20-tetranorprostanoate), IR 1740 cm⁻¹ (esterand ketone carbonyls), NMR (CCl₄) δ 1.0 ppm (multiplet, terminal methylgroup).

EXAMPLE 90 Preparation of cis-5-octen-1-yne

A 57% sodium hydride dispersion (9.66 g., 0.23 mole) is washed free ofmineral oil in a nitrogen atmosphere with hexane. The hydride is heatedat 75° C. with 220 ml. of dimethyl sulfoxide for 45 minutes. Theresulting green solution is cooled to 18° C. and treated with a solutionof 4-pentynyl-triphenylphosphonium iodide (100 g., 0.22 mole) in 220 ml.of dimethylsulfoxide over a 25 minute period. The resulting red solutionis stirred at ambient temperature for 45 minutes. To the solution isadded a solution of freshly distilled propionaldehyde (14.0 g., 0.24mole) in 10 ml. of dimethylsulfoxide over a ten minute period at 25° C.After standing at room temperature, the reaction is quenched withhalf-saturated brine and brought to pH 4 with 4N HCl. The product isextracted with an ether-hexane mixture, and the extract is washedsuccessively with water and brine, dried over MgSO₄, and concentrated.The crude product is fractionated with a spinning band column to give acolorless distillate, b.p. 121-122° C., IR 3270, 2110 and 1645 cm⁻¹.

EXAMPLE 91 Preparation of ethyl 9-oxo-13-trans-17-cis-prostadienoate

In the manner described in Example 85,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to thereagent prepared from cis-5-octen-1-yne (Example 90), diisobutylaluminumhydride, and n-butyl lithium. The crude product, obtained by acidhydrolysis and evaporation of the organic solvent, is purified bydistillation to give an oil, IR 1740 cm⁻¹ (ester and ketone carbonyls)and 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 92 Preparation of ethyl 9-oxo-6,7-dinor-13-trans-prostenoate

In the manner described in Example 80,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride, and methyllithium. The product is obtained by acid hydrolysis, ether extractionand distillation to yield a colorless oil, b.p. 149°-150° C. (0.075mm.). IR 1740 cm⁻¹ (ester and ketone carbonyls) 963 cm⁻¹ (trans-vinylgroup).

EXAMPLE 93 Preparation of ethyl 20-chloro-9-oxo-6,7-diner-13-transprostenoate

In the manner described in Example 85,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 8-chloro-1-octyne, diisobutylaluminum hydride, andn-butyl lithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls) 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 94 Preparation of ethyl 9-oxo-6,7,20-trinor-13-trans-prostenoate

In the manner described in Example 802-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 1--heptyne, diisobutylaluminum hydride and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls) 967 cm⁻¹ (trans vinyl group).

EXAMPLE 95 Preparation of ethyl9-oxo-6,7-dinor-13-trans-17-cis-prostadienoate

In the manner described in Example 91,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminumhydride, and n-butyl lithium. The crude product obtained by acidhydrolysis and ether extraction is purified by silica gel chromatographyto give an oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) 967 cm⁻¹(trans-vinyl group).

EXAMPLE 96 Preparation of ethyl20-chloro-9-oxo-6,7,17,18,19-pentanor-13-trans-prostenoate

In the manner described in Example 85,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride,and n-butyl lithium. The crude product obtained by acid hydrolysis andether extraction is purified by silica gel chromatography to give anoil, IR 1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinylgroup).

EXAMPLE 97 Preparation of ethyl17-methyl-9-oxo-6,7,19,20-tetranor-13-trans-prostenoate

In the manner described in Example 85,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 5-methyl-1-hexyne, diisobutylaluminum hydride andn-butyl lithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 98 Preparation of ethyl9-oxo-13-propyl-6,7,18,19,20-pentanor-13-trans-prostenoate

In the manner described in Example 80,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) is added to thereagent prepared from 4-octyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls).

EXAMPLE 99 Preparation of ethyl 9-oxo-5,6,7-trinor-13-trans-prostenoate

In the manner described in Example 80,2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 100 Preparation of ethyl9-oxo-20-propyl-5,6,7-trinor-13-trans-prostenoate

In the manner described in Example 80,2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) is added to thereagent prepared from 1-undecyne, diisobutylaluminum hydride and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 101 Preparation of ethyl9-oxo-5,6,7,18,19,20-hexanor-13-trans-prostenoate

In the manner described in Example 80,2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) is added to thereagent prepared from 1-pentyne, dissobutylaluminum hydride and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 102 Preparation of ethyl20-chloro-9-oxo-5,6,7-trinor-13-trans-prostenoate

In the manner described in Example 80,2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) is added to thereagent prepared from 8-chloro-1-octyne, diisobutylaluminum hydride, andmethyl lithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 103 Preparation of ethyl9-oxo-7a,7b-bis-homo-13-trans-prostenoate

In the manner described in Example 80,2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 23) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 104 Preparation of ethyl20-chloro-9-oxo-7a,7b-bis-homo-17,18,19,-trinor-13-trans-prostenoate

In the manner described in Example 85,2-(8carbethoxypropyl)-2-cyclopentenone (Example 23) is added to thereagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride,and n-butyl lithium. The crude product obtained by acid hydrolysis andether extraction is purified by silica gel chromatography to give anoil, IR 1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinylgroup).

EXAMPLE 105 Preparation of ethyl20-butyl-9-oxo-7a,7b-bis-homo-13-trans-prostenoate

In the manner described in Example 80,2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 23) is added to thereagent prepared from 1-dodecyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 106 Preparation of ethyl15-methyl-9-oxo-7a,7b-bis-homo-17,18,19,20-tetranor-13-trans-prostenoate

In the manner described in Example 80,2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 23) is added to thereagent prepared from 3-methyl-1-butyne, diisobutylaluminum hydride, andmethyl lithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 107 Preparation of ethyl20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate

A stirred mixture of 51.5 g. of ethyl20-chloro-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 88), 30 g.of sodium iodide, and 250 ml. of acetone is refluxed for 10 hours. Anadditional 10 g. of sodium iodide is added, and the reaction iscontinued for 2 hours. The reaction mixture is filtered, concentrated toa volume of 150 ml., diluted with water, and extracted with ether. Theextract is washed with saturated sodium chloride, dried, and evaporatedto give an oil.

EXAMPLE 108 Preparation of ethyl 20-iodo-9-oxo-13-trans-prostenoate

A stirred mixture of 30 g. of ethyl 20-chloro-9-oxo-13-trans-prostenoate(Example 84), 25 g. of sodium iodide and 225 ml. of acetone is refluxedfor 12 hours. The reaction mixture is concentrated, diluted with water,and extracted with ether. The extract is washed with saturated sodiumchloride, dried, and evaporated to give an oil.

EXAMPLES 109-112

Treatment of the corresponding 20-chloroprostenoate or20-chloro-17,18,19-trinor-prostenoate with sodium iodide in acetone bythe procedure of Example 107 provides the 20-iodo derivatives of TableIV below.

                  TABLE IV                                                        ______________________________________                                                 Starting 20-                                                                  Chloro-Deriva-                                                       Example  tive of Example                                                                              Product                                               ______________________________________                                        109       93            ethyl 20-iodo-9-oxo-6,7-                                                      dinor-13-trans-                                                               prostenoate                                           110       96            ethyl 20-iodo-9-oxo-6,7-                                                      17,18,19-pentanor-13-                                                         trans-prostenoate                                     111      102            ethyl 20-iodo-9-oxo-5,6,                                                      7-trinor-13-trans-                                                            prostenoate                                           112      104            ethyl 20-iodo-9-oxo-7a,                                                       7b,-dihomo-17,18,19-tri-                                                      nor-13-trans-prostenoate                              ______________________________________                                    

EXAMPLE 113 Preparation of ethyl 9-oxo-18-thia-13-trans-prostenoate

To 6.0 ml. of a stirred, ice-cold solution of 0.5M 5-ethylisothiouroniumiodide in 10:1 ethanol:water is added 264 mg. of sodium hydroxidedissolved in 2.0 ml. of ethanol and 4.0 ml. of water. The mixture isstirred under nitrogen at ambient temperature for 15 min. and thencooled in the ice bath while a solution of ethyl20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (434 mg.) (Example107) in 3 ml. of ethanol is added. The reaction mixture is stirredsuccessively at 0° for 15 min., at ambient temperature for 15 min., andat 40° for 5 min. The mixture is diluted with water and extracted withether. The extract is washed successively with water and saturatedsodium chloride, dried, and evaporated. The crude product is purified bychromatography on silica gel to give an oil, IR 1740 cm⁻¹ (ester andketone carbonyls) and 967 cm⁻¹ (trans vinyl group); NMR (CCl₄) δ2.47 ppm(multiplet, methylenethio groups).

EXAMPLES 114-115

Treatment according to the procedure of Example 113, of the various20-iodo-17,18,19-trinor-trans-prostenoates of Table V (below) withsodium ethyl mercaptide (prepared in situ as in Example 113) isproductive of the various 18-thiaprostenoates of the Table.

                  TABLE V                                                         ______________________________________                                                 Starting 20-                                                                  Iodoprostenoate                                                                              Product                                               Example  of Example     18-Thiaprostenoate                                    ______________________________________                                        114      110            ethyl 9-oxo-18-thia-                                                          6,7-dinor-13-trans-                                                           prostenoate                                           115      112            ethyl 9-oxo-18-thia-                                                          7a,7b-bis-homo-13-                                                            trans-prostenoate                                     ______________________________________                                    

EXAMPLE 116 Preparation of ethyl 9-oxo-18-oxythia-13-trans-prostenoate

To a stirred, ice-cold solution of the 18-thiaprostenoate of Example 113(11.5 g., 31 mmole) in 150 ml. of ethanol is added a solution of sodiummetaperiodate (6.65 g., 31.2 mmole) in 55 ml. of water during a twentymin. period. The mixture is allowed to stand at 10° C. for 17 hours.Excess periodate is destroyed by the addition of one ml. of ethyleneglycol, and the mixture is filtered. The filtrate is concentrated toone-third of the original volume, diluted with water, and extracted withether. The extract is washed with brine, dried over MgSO₄, andconcentrated. Column chromatography of the residue on silica gel withcholoroform-ether mixture gives an oil, IR 1740 (ether and ketonecarbonyls), 1040 (sulfoxide), and 967 cm⁻¹ (trans vinyl group).

EXAMPLE 117 Preparation of ethyl9-oxo-18-oxythia-7a,7b-bis-homo-13-trans-prostenoate

Treatment of the sulfide of Example 115 with sodium metaperiodate by theprocedure of Example 116 is productive of the subject sulfoxide.

EXAMPLE 118 Preparation of ethyl20,20-dicarbethoxy-9-oxo-18,19-dinor-13-trans-prostenoate

To a solution of sodium ethoxide, prepared from 426 mg. of sodium, in 20ml. of ethanol is added a solution of 3.96 g. of diethyl malonate in 10ml. of ethanol over a 10 min. period. After stirring for 45 min., asolution containing 5.21 g. of ethyl20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 107) in 10ml. of ethanol is added, and the resulting solution is refluxed for 16hours. The solution is concentrated to one-third of the original volume,diluted with 50 ml. of ether, and treated with 40 ml. of 0.2N HCl. Theether phase is washed with brine, dried over MgSO₄, and concentrated.Column chromatography of the residue on silica gel with chloroform-ethermixtures gives an oil, IR 1740 (ester and ketone carbonyls) and 967 cm⁻¹(trans vinyl group); nmr 3.2 δ (triplet, alkyl-malonate methinehydrogen)

EXAMPLE 119 Preparation of ethyl20,20-dicarbethoxy-9-oxo-6,7,18,19-tetranor-13-trans-prostenoate

Treatment of the ethyl20-iodo-9-oxo-6,7,17,18,19-pentanor-13-trans-prostenoate of Example 110with diethyl sodio malonate by the procedure of Example 118 isproductive of the product.

EXAMPLE 120 Preparation of ethyl9,9-ethylenedioxy-20-iodo-17,18,19-trinor-13-trans-prostenoate

A solution of 25.2 g. of ethyl20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 107), 5.6ml. of ethylene glycol and 110 mg. of p-toluenesulfonic acid monohydratein 170 ml. of benzene is refluxed for 4 hours with azetropic removal ofwater. The solution is concentrated to a volume of 50 ml. Columnchromatography of the solution on Florisil® with benzene gives a liquid,IR 1740 (ester carbonyl), 967 (trans vinyl group), and 952 cm⁻¹(ethylene ketal).

EXAMPLES 121-122

Ketalization with ethylene glycol in the presence of p-toluenesulfonicacid of the appropriate 20-iodo-9-oxo-prostenoates by the procedure ofExample 120 provides the ketals of Table VI, which follows.

                  TABLE VI                                                        ______________________________________                                                 Starting Ketone                                                      Example  of Example     Product                                               ______________________________________                                        121      110            ethyl 9,9-ethylenedioxy-                                                      20-iodo-6,7,17,18,19-                                                         pentanor-13-trans-                                                            prostenoate                                           122      108            ethyl 9,9-ethylenedioxy-                                                      20-iodo-13-trans-                                                             prostenoate                                           ______________________________________                                    

EXAMPLE 123

Preparation of ethyl 9,9-ethylenedioxy-18-oxa-13-trans-prostenoate

To a stirred, ice-cold suspension of 1.68 g. of 57% sodium hydride inoil and 20 ml. of dimethylformamide (DMF) is added a solution of 2.5 ml.of ethanol in 5 ml. of DMF over a 15 min. period. The mixture evolvesgas and is stirred at room temperature for 45 min. To the resultingsuspension is added a solution of 9.57 g. of ethyl9,9-ethylenedioxy-20-iodo-17,18,19-trinor-13-trans-prostenoate (Example120) in 15 ml. of DMF over a 10 min. period at 10°-15° C. The resultingdark mixture is stirred at ambient temperature for 45 min. and thenpoured into 200 ml. of ice water. The mixture is brought to pH 7 with 4NHCl and extracted with ether. The extract is washed with brine, driedover MgSO₄, and concentrated. Column chromatography of the residue onsilica gel with benzene-ether mixtures gives a liquid, IR 1740 (estercarbonyl), 967 (trans vinyl group), and 952 cm⁻¹ (ethylene ketal); nmr3.4 δ (triplet superimposed on quartet, O-methylene ether groups).

EXAMPLE 124 Preparation of ethyl9,9-ethylenedioxy-20-phthalimido-13-trans-prostenoate

A stirred mixture of 8.80 g. of ethyl9,9-ethylenedioxy-20-iodo-13-trans-prostenoate (Example 122), 3.28 g. ofpotassium phthalimide, and 25 ml. of DMF is heated at 70° C. for 2hours. The cooled mixture is diluted with water and extracted withether. The extract is washed with brine, dried over potassiumbicarbonate, and concentrated to give an oil, IR 1770 (phthalimidegroup), 1735 (ester carbonyl group), 1710 (phthalimide group), 967(trans vinyl group), and 950 cm⁻¹ (ethylene ketal).

EXAMPLE 125 Preparation of 20-amino-9-oxo-13-trans-prostenoic acidhydrochloride

A stirred mixture of 9.3 g. of ethyl9,9-ethylenedioxy-20-phthalimido-13-trans-prostenoate (Example 124),2.25 g. of potassium hydroxide, 85 ml. of methanol, and 1.0 ml. of wateris refluxed for 2 hours. After addition of 2.25 g. of potassiumhydroxide and 2.0 ml. of water, the mixture is refluxed for anadditional one hour. The solution is concentrated to remove methanol,and the residue with 75 ml of 4N HCl for 18 hours. The upper phase ofthe resulting two-phase system is dissolved in water and concentrated togive an oil, IR 1730 (ketone carbonyl group), 1710 (acid carbonylgroup), and 967 cm⁻¹ (trans vinyl group).

EXAMPLE 126 Preparation of ethyl9,9-ethylenedioxy-20-pyrrolidino-17,18,19-trinor-13-trans-prostenoate

A mixture of 4.17 g. of potassium carbonate, 9.95 g. of pyrrolidine, and55 ml. of dimethylformamide (DMF) is stirred at 50° C. To the mixture isadded a solution of 13.5 g. of ethyl9,9-ethylenedioxy-20-iodo-17,18,19-trinor-13-trans-prostenoate (Example120) in 15 ml. of DMF over a 40 min. period. After an additional 30 min.at 50° C. the mixture is cooled and treated with 200 ml. of water. Themixture is extracted with 5:1 (v/v) ether:hexane. The extract is washedwith brine, dried with potassium carbonate, and concentrated. Columnchromatography of the residue on Florisil® with benzene-ether mixturesgives an oil, IR 1740 (ester carbonyl group), 967 (trans vinyl group),and 950 cm⁻¹ (ethylene ketal).

EXAMPLES 127-129

Treatment of the iodoprostenoate ketals of Table VII (below) by theprocedure of Example 126 with the indicated amine is productive of theaminoprostenoate ketals of the table.

                  TABLE VII                                                       ______________________________________                                                 Starting                                                                      Iodopros-                                                            Ex-      tenoate              Aminoprostenoate                                ample    of Example Amine     Product                                         ______________________________________                                        127      121        piperi-   ethyl 9,9-ethyl-                                                    dine      enedioxy-20-piperi-                                                           dino-6,7,17,18,19-                                                            pentanor-13-trans-                                                            prostenoate                                     128      120        morpho-   ethyl 9,9-ethyl-                                                    line      enedioxy-20-mor-                                                              pholino-17,18,19-                                                             trinor-13-trans-                                                              prostenate                                      129      122        pyrroli-  ethyl 9,9-ethyl-                                                    dine      enedioxy-20-                                                                  pyrrolidino-13-                                                               trans-prosteno-                                                               ate                                             ______________________________________                                    

EXAMPLE 130 Preparation of 20-mercapto-9-oxo-13-trans-prostenoic acid

A solution of 9.53 g. of ethyl 20-iodo-9-oxo-13-trans-prostenoate(Example 108) and 1.60 g. of thiourea in 20 ml. of ethanol is refluxedfor 45 min. The resulting solution of the correspondng20-S-isothiouronium salt is diluted with 140 ml. of methanol and asolution of 5.30 g. of potassium hydroxide in 20 ml. of water. Theresulting solution is allowed to stand at room temperature for 19 hours.The solution is concentrated to a volume of 100 ml. and diluted with 200ml. of water. The solution is acidified with 4N HCl and extracted withether. The extract is washed with brine, dried over MgSO₄, andconcentrated. Column chromatography of the residue on silica gel withchloroform-ether mixtures gives an oil, IR 1740 (ketone carbonyl), 1710(acid carbonyl), and 967 cm⁻¹ (trans vinyl group); mnr 2.4 δ (methylenethiol group).

EXAMPLE 131 Preparation of20-mercapto-9-oxo-6,7-dinor-13-trans-prostenoic acid

Treatment of the 20-iodoprostenoate of Example 109 according to theprocedure of Example 130, with thiourea produces the corresponding20-S-isothiouronium salt, which on treatment with sodium hydroxidesolution is productive of the 20-mercapto derivative.

EXAMPLE 132 Preparation of9-oxo-20-pyrrolidino-17,18,19-trinor-13-trans-prostenoic acid

A stirred mixture of 9.20 g. of ethyl9,9-ethylenedioxy-20-pyrrolidino-17,18,19-trinor-13-trans-prostenoate(Example 126), 0.02 ml. of concentrated sulfuric acid, 35 ml. of glacialacetic acid, and 17.5 ml. of water is refluxed for 17 hours. The cooledreaction mixture is treated with 58 mg. of sodium bicarbonate andconcentrated to near-dryness. The residue is treated with water andextracted with ether. The ether phase is back-extracted wtih 0.1N HCl,and all aqueous phases are concentrated to give the subject amino acid.

EXAMPLES 133-135

Hydrolysis of the aminoprostenoate ketals of Table VIII below by theprocedure of Example 132 is productive of the aminoprostenoic acids ofthe table.

                  TABLE VIII                                                      ______________________________________                                                 Starting Amino-                                                      Ex-      prostenoate Ketal                                                                           Product                                                ample    of Example    Aminoprostenoic Acid                                   ______________________________________                                        133      127           9-oxo-20-piperidino-                                                          6,7,17,18,19-penta-                                                           nor-13-trans-prostenoic                                                       acid                                                   134      128           20-morpholino-9-oxo-                                                          17,18,19-trinor-13-                                                           trans-prostenoic acid                                  135      129           9-oxo-20-pyrrolidino-                                                         13-trans-prostenoic                                                           acid                                                   ______________________________________                                    

EXAMPLES 138-141

Treatment of 2-(6-carbethoxyoctyl)-2-cyclopentenone (Example 31) in themanner of Example 80 with the reagents prepared from the alkyneindicated in Table IX below, diisobutyl aluminum hydride and methyllithium is productive of the prostenoate esters of the first threeExamples of this table. Saponification of the ester by the procedure ofExample 151 provides the corresponding prostenoic acids.

                  TABLE IX                                                        ______________________________________                                                  Starting Alkyne                                                     Ex-       or Prostenoate                                                      ample     Ester         Product                                               ______________________________________                                        136       1-octyne      ethyl 2-ethyl-9-oxo-                                                          13-trans-prostenoate                                  137       cis-5-octen-1-                                                                              ethyl 2-ethyl-9-oxo-                                            yne           13-trans-17-cis-                                                              prostadienoate                                        138       8-chloro-1-   ethyl 2-ethyl-9-oxo-                                            octyne        20-chloro-13-trans-                                                           prostenoate                                           139       Example 136   2-ethyl-9-oxo-13-trans-                                                       prostenoic acid                                       140       Example 137   2-ethyl-9-oxo-13-trans-                                                       17-cis-prostadienoic                                                          acid                                                  141       Example 138   2-ethyl-9-oxo-20-                                                             chloro-13-trans-                                                              prostenoic acid                                       ______________________________________                                    

EXAMPLE 142 Preparation of ethyl 9α- and 9β-hydroxy-13-trans-prostenoate

A solution of 1 g. of ethyl 9-oxo-13-trans-prostenoate (Example 80) in40 ml. of absolute alcohol containing 41 mg. of sodium borohydride isstirred at room temperature (protected from moisture) for 19 hours. Themixture is poured into 100 ml. of water and the resulting solution isextracted several times with ether. The combined ether extracts arewashed several times with saturated sodium chloride solution, dried withanhydrous magnesium sulfate and taken to dryness to give 806 mg. of anoil. Distillation furnished 700 mg. (70%) of product as a pale yellowoil; b.p. 179° C. (0.13 mm); λ_(max) 2.98, 5.78, 5.81 (shoulder), 8.50,10.30 μ; nmr 2H multiplet δ5.36 (olefinic protons), 2H triplet 4.13(OCH₂ of ester), 3H distorted triplet 1.23 (methyl of ester) and 3Hdistorted triplet 0.90 (terminal methyl).

EXAMPLES 143-150

The following alcohols (as mixtures of 9α- and 9β-epimers) of Table Xare prepared by sodium borohydride reduction of the corresponding9-ketones according to the procedure of Example 142.

                  TABLE X                                                         ______________________________________                                        Exam-     Starting Ketone                                                     ple       of Example   Product                                                ______________________________________                                        143       88           ethyl 9-hydroxy-20-                                                           chloro-17,18,19-tri-                                                          nor-13-trans-proste-                                                          noate                                                  144       87           ethyl 9-hydroxy-17-                                                           methyl-18,19-dinor-                                                           13-trans-prostenoate                                   145       92           ethyl 9-hydroxy-6,7-                                                          dinor-13-trans-pro-                                                           stenoate                                               146       102          ethyl 9-hydroxy-20-                                                           chloro-5,6,7-trinor-                                                          13-trans-prostenoate                                   147       105          ethyl 9-hydroxy-20-                                                           butyl-7a,7b-bis-homo-                                                         13-trans-prostenoate                                   148       113          ethyl 9-hydroxy-18-                                                           thia-13-trans-proste-                                                         noate                                                  149       106          ethyl 9-hydroxy-15-                                                           methyl-7a,7b-bis-homo-                                                        17,18,19,20-tetranor-                                                         13-trans-prostenoate                                   150       89           ethyl 9-hydroxy-13-                                                           propyl-18,19,20-tri-                                                          nor-13-trans-proste-                                                          noate                                                  ______________________________________                                    

EXAMPLE 151 Preparation of 20-butyl-9-oxo-13-trans-prostenoic acid

A solution of 2.33 g. of ethyl 20-butyl-9-oxo-13-trans-prostenoate(Example 81) and 1.30 g. of potassium hydroxide in 35 ml. of methanoland 3.51 ml. of water is allowed to stand at room temperature for 24hours. The reaction mixture is concentrated in vacuo, diluted withwater, and washed with ether. The aqueous phase is acidified to pH 2 andextracted with ether. The extract is washed with saturated sodiumchloride, dried, and evaporated to give an oil, IR 1745 cm⁻¹ (ketonecarbonyl), 1710 cm⁻¹ (acid carbonyl), and 967 cm⁻¹ (trans vinyl group).

EXAMPLE 152 Preparation of 9-oxo-13-trans-prostenoic acid

A mixture of 0.140 g. of ethyl 9-oxo-13-trans-prostenoate (Example 80)and 0.072 g. of potassium hydroxide in 6 ml. of 1:1 aqueous methanol isstirred at ambient temperature for 17 hours. The resulting solution isacidified with hydrochloric acid, extracted with diethyl ether, and theorganic phase is washed with water and saturated brine, dried, and thesolvent removed to yield 0.128 g. of an oil, IR 1739 cm⁻¹ (ketonecarbonyl) 1706 cm⁻¹ (acid carbonyl), 969 cm⁻¹ (trans vinyl group); NMR(CDCl₃) 5.34-5.67 (multiplet, 2H, vinyl protons, J trans=15 Hz), 10.47(broad singlet, 1H, carboxyl proton, exchangeable); Mass spectrum,parent peak at 322 mu.

EXAMPLE 153 Preparation of 9-oxo-6,7-dinor-13-trans-prostenoic acid

In the manner described in Example 152, ethyl9-oxo-6,7-dinor-13-trans-prostenoate (Example 92) is saponified withpotassium hydroxide, acidified, and worked-up by ether extraction andevaporative distillation at 160° C. (0.005 Torr) to yield a colorlessoil.

EXAMPLE 154 Preparation of 9α- and 9β-hydroxy-13-trans-prostenoic acid

A suspension of 1.8 g. of ethyl 9α- and 9β-hydroxy--13-trans-prostenoate(Example 142) in 40 ml. of aqueous methanol (1:1) containing 890 mg. ofpotassium hydroxide is stirred at ambient temperature for 18 hours. Theresulting solution is cooled, acidified with 1N hydrochloric acid andextracted several times with ether. The combined ether extracts arewashed with sodium chloride solution, dried with anhydrous magnesiumsulfate, and taken to dryness to give 1.61 g. (98%) of product as anoil; λmax 2.95, 3,40, 3.75, 5.85, 10.31 μ; nmr 2H singlet δ 6.10(hydroxyl and carboxyl protons), 2H multiplet 5.40 (olefinic protons),and 3H distorted triplet 0.90 (terminal methyl).

EXAMPLES 155-190

In the manner described in Example 151, the carboxylic acids of Table XI(below) are prepared by saponification of the corresponding ethyl estersat room temperature in methanol-water followed by acidification andextraction with ether. Infrared characterization of the cyclopentanonederivatives gives bands at about 1745 cm⁻¹ (ketone carbonyl), 1710 cm⁻¹(acid carbonyl) and 967 cm⁻¹ (trans vinyl group).

                  TABLE XI                                                        ______________________________________                                        Exam-     Starting Ester                                                      ple       of Example   Product                                                ______________________________________                                        155       82           9-oxo-18,19,20-trinor-                                                        13-trans-prostenoic                                                           acid                                                   156       83           15-methyl-9-oxo-17,18,-                                                       19,20-tetranor-13-                                                            trans-prostenoic acid                                  157       84           20-chloro-9-oxo-13-                                                           trans-prostenoic acid                                  158       85           9-oxo-20-nor-13-trans-                                                        prostenoic acid                                        159       86           20-methyl-9-oxo-13-                                                           trans-prostenoic acid                                  160       87           17-methyl-9-oxo-19,20-                                                        dinor-13-trans-pro-                                                           stenoic acid                                           161       88           20-chloro-9-oxo-17,18-                                                        19-trinor-13-trans-                                                           prostenoic acid                                        162       89           9-oxo-13-propyl-18,19,-                                                       20-trinor-13-trans-                                                           prostenoic acid                                        163       91           9-oxo-13-trans-17-cis-                                                        prostadienoic acid                                     164       93           20-chloro-9-oxo-6,7-                                                          dinor-13-trans-pro-                                                           stenoic acid                                           165       94           9-oxo-6,7,20-trinor-                                                          13-trans-prostenoic                                                           acid                                                   166       95           9-oxo-6,7-dinor-13-                                                           trans-17-cis-prosta-                                                          dienoic acid                                           167       96           20-chloro-9-oxo-6,7,-                                                         17,18,19-pentanor-13-                                                         trans-prostenoic acid                                  168       97           17-methyl-9-oxo-6,7,-                                                         19,20-tetranor-13-                                                            trans-prostenoic acid                                  169       98           9-oxo-13-propyl-6,7,18,-                                                      19,20-pentanor-13-                                                            trans-prostenoic acid                                  170       99           9-oxo-5,6,7-trinor-13-                                                        trans-prostenoic acid                                  171       100          9-oxo-20-propyl-5,6,7-                                                        trinor-13-trans-pro-                                                          stenoic acid                                           172       101          9-oxo-5,6,7,18,19,20-                                                         hexanor-13-trans-pro-                                                         stenoic acid                                           173       102          20-chloro-9-oxo-5,6,7-                                                        trinor-13-trans-pro-                                                          stenoic acid                                           174       103          9-oxo-7a,7b-bis-homo-                                                         13-trans-prostenoic                                                           acid                                                   175       104          20-chloro-9-oxo-7a,7b-                                                        bis-homo-17,18,19-tri-                                                        nor-13-trans-prostenoic                                                       acid                                                   176       105          20-butyl-9-oxo-7a,7b-                                                         bis-homo-13-trans-pro-                                                        stenoic acid                                           177       106          15-methyl-9-oxo-7a,7b-                                                        bis-homo-17,18,19,20-                                                         tetranor-13-trans-pro-                                                        stenoic acid                                           178       113          9-oxo-18-thia-13-trans-                                                       prostenoic acid                                        179       114          9-oxo-18-thia-6,7-di-                                                         nor-13-trans-prostenoic                                                       acid                                                   180       115          9-oxo-18-thia-7a,7b-                                                          bis-homo-13-trans-pro-                                                        stenoic acid                                           181       116          9-oxo-18-oxythia-13-                                                          trans-prostenoic acid                                  182       117          9-oxo-18-oxythia-7a,-                                                         7b-bis-homo-13-trans-                                                         prostenoic acid                                        183       143          9-hydroxy-20-chloro-                                                          17,18,19-trinor-13-                                                           trans-prostenoic acid                                  184       144          9-hydroxy-17-methyl-18-                                                       19-dinor-13-trans-pro-                                                        stenoic acid                                           185       145          9-hydroxy-6,7-dinor-                                                          13-trans-prostenoic                                                           acid                                                   186       146          9-hydroxy-20-chloro-                                                          5,6,7-trinor-13-                                                              trans-prostenoic acid                                  187       147          9-hydroxy-20-butyl-7a,-                                                       7b-bis-homo-13-trans-                                                         prostenoic acid                                        188       148          9-hydroxy-18-thia-13-                                                         trans-prostenoic acid                                  189       149          9-hydroxy-15-methyl-                                                          7a,7b-bis-homo-17,18,-                                                        19,20-tetranor-13-                                                            trans-prostenoic acid                                  190       150          9-hydroxy-13-propyl-18-                                                       19,20-trinor-13-trans-                                                        prostenoic acid                                        ______________________________________                                    

EXAMPLE 191 Preparation of20-carboxy-9-oxo-18,19-dinor-13-trans-prostenoic acid

A solution of ethyl20,20-dicarbethoxy-9-oxo-18,19--dinor-13-trans-prostenoate (Example118), prepared from 10.42 g. of iodo compound (Example 107), isdissolved in 240 ml. of methanol and treated with a solution of 9.50 g.of potassium hydroxide in 24 ml. of water. The solution is allowed tostand at room temperature for 42 hours. Most of the methanol is removedin vacuo, and the residue is dissolved in 200 ml. of water. Afteracidification with 4N HCl the acidic product is extracted with ether.The extract is washed with brine, dried over MgSO₄, and evaporated. Theresidue is heated at 120° C. for 1.5 hours and subjected to columnchromatography on silica gel with chloroform ether mixtures to give anoil, IR 1745 cm⁻¹ (ketone carbonyl), 1715 cm⁻¹ (acid carbonyl), and 967cm⁻¹ (trans vinyl group).

EXAMPLE 192 Preparation of20-carboxy-9-oxo-6,7,18,19-tetranor-13-trans-prostenoic acid

Hydrolysis and decarboxylation, according to the procedure of Example191, of ethyl20,20-dicarbethoxy-9-oxo-6,7,18,19-tetranor-13-trans-prostenoate(Example 119) provides the product.

EXAMPLE 193 Preparation of ethyl 18-oxa-9-oxo-13-trans-prostenoate

A solution of 1.07 g. of ethyl9,9-ethylenedioxy-18-oxa-13-trans-prostenoate (Example 123) and 27 mg.of toluenesulfonic acid monohydrate in 10 ml. of acetone is allowed tostand at room temperature for 17 hours. The bulk of the acetone isevaporated, and the residue is treated with 25 ml. of water andextracted with ether. The extract is washed successively with diluteNaHCO₃ and brine and dried over MgSO₄. Evaporation of the solvent givesan oil, IR 1740 (ester and ketone carbonyls) and 967 cm⁻¹ (trans vinylgroup).

EXAMPLE 194 Preparation of 18-oxa-9-oxo-13-trans-prostenoic acid

Saponification of ethyl 18-oxa-9-oxo-13-trans-prostenoate (Example 193)by the procedure of Example 151 is productive of the product.

EXAMPLE 195 Preparation of 3'-pyridyl 9-oxo-13-trans-prostenoate

9-Oxo-13-trans-prostenoic acid (Example 152) is converted to9-oxo-13-trans-prostenoyl chloride by treatment with thionyl chloride. Abenzene solution of 9-oxo-13-trans-prostenoyl chloride (24.8 moles) isslowly added to a slight excess of 3-hydroxypyridine (26 moles) in 100ml. of benzene containing 5 ml. of triethylamine. The mixture ismagnetically stirred and refluxed for 30 min. The reaction mixture isfiltered and taken to dryness and the residue is dissolved in ether andwashed successively with saline, dilute sodium bicarbonate solution,dried and taken to dryness. The oil is purified by adsorptionchromatography on a magnesia-silica gel column and eluted with benzeneto give a dark yellow oil.

EXAMPLES 196-197

In the manner described in Example 195, the various prostenoic acids ofthe following table are converted with thionyl chloride to thecorresponding prostenoyl chlorides and thence with the indicatedalcohols to the various prostenoic acid esters of Table XII, whichfollows.

                  TABLE XII                                                       ______________________________________                                                 Starting Pros-                                                       Ex-      tenoic Acid of                                                       ample    Example      Alcohol   Product                                       ______________________________________                                        196      171          methanol  methyl 9-oxo-                                                                 20-propyl-5,                                                                  6,7-trinor-                                                                   13-trans-pro-                                                                 stenoate                                      197      152          n-butnaol n-butyl 9-oxo-                                                                13-trans-                                                                     prostenoate                                   ______________________________________                                    

EXAMPLE 198 Preparation of ethyl 9-oxo-3-thia-13-trans-prostenoate

In the manner described in Example 80, treatment of2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone (Example 40) with thereagent prepared from 1-octyne, diisobutylaluminum hydride and methyllithium gives the subject 3-thiaprostenoate as a yellow oil.

EXAMPLE 199 Preparation of ethyl 3-oxa-9-oxo-13-trans-prostenoate

In the same manner as for the preparation of the compound of Example 80,ethyl 3-oxa-9-oxo-13-trans-prostenoate is prepared by the addition of2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone (Example 36) to the reagentprepared from 1-octyne, diisobutylaluminum hydride and methyl lithium.

EXAMPLES 200-207

In the manner of Example 80, treatment of the oxa or thia cyclopentenoneesters of Examples 36 and 40, respectively, with the alanate complexobtained from the alkynes indicated in Table XIII below,diisobutylaluminum hydride and methyl lithium, is productive of the3-oxa or 3-thia prostenoates of the Table.

                  TABLE XIII                                                      ______________________________________                                        Examp-   Starting Cyclo-                                                                           Starting                                                 ple      pentenone   Alkyne    Product                                        ______________________________________                                        200      2-(6-carbeth-                                                                             8-chloro- ethyl 20-chloro-                                        oxy-5-oxahex-                                                                             1-octyne  3-oxa-9-oxo-13-                                         yl)-2-cyclo-          trans-prosteno-                                         pentenone             ate                                            201      2-(6-carbeth-                                                                             5-chloro- ethyl 20-chloro-                                        oxy-5-oxahex-                                                                             1-pen-    3-oxa-9-oxo-17,-                                        yl)-2-cyclo-                                                                              tyne      18,19-trinor-13-                                        pentenone             trans-prosteno-                                                               ate                                            202      2-(6-carbeth-                                                                             cis-5-    ethyl 3-oxa-9-                                          oxy-5-oxahex-                                                                             octen-1-  oxo-13-trans-                                           yl)-2-cyclo-                                                                              yne       17-cis-prosta-                                          pentenone             dienoate                                       203      2-(6-carbeth-                                                                             1-nonyne  ethyl 20-methyl-                                        oxy-5-oxahex-         3-oxa-9-oxo-13-                                         yl)-2-cylco-          trans-prosteno-                                         pentenone             ate                                            204      2-(6-carbeth-                                                                             8-chloro- ethyl 20-chloro-                                        oxy-5-thiahex-                                                                            1-octyne  9-oxo-3-thia-                                           yl)-2-cyclo-          13-trans-proste-                                        pentenone             noate                                          205      2-(6-carbeth-                                                                             5-chloro- ethyl 20-chloro-                                        oxy-5-thiahex-                                                                            1-pen-    9-oxo-3-thia-                                           yl)-2-cyclo-                                                                              tyne      17,18,19-tri-                                           pentenone             nor-13-trans-pro-                                                             stenoate                                       206      2-(6-carbeth-                                                                             cis-5-    ethyl 9-oxo-3-                                          oxy-5-thiahex-                                                                            octen-1-  thia-13-trans-                                 2-cyclo- yne         17-cis-prosta-                                                    pentenone             dienoate                                       207      2-(6-carbeth-                                                                             1-hexyne  ethyl 9-oxo-3-                                          oxy-5-thiahex-        thia-19,20-di-                                          yl)-2-cyclo-          nor-13-trans-                                           pentenone             prostenoate                                    ______________________________________                                    

EXAMPLE 208 Preparation of2-carbalkoxy(methyl/ethyl)-2-(carbethoxymethyl)cyclopentan-1-one

In the manner desribed in Example 1, treatment ofcyclopentanone-2-carboxylate (mixed methyl and ethyl esters) with sodiumhydride in dimethoxyethane followed by ethyl bromoacetate providing ayellow oil, b.p. 130°-190° C. (7 mm).

EXAMPLE 209 Preparation of 2-(carboxymethyl)cyclopentan-1-one

In the manner described in Example 2, the2-carbaloxy-2-carbethoxymethylcyclopentanone of Example 208 isdecarbalkoxylated to provide 2-carboxymethylcyclopentan-1-one.

EXAMPLE 210 Preparation of 2-carbethoxymethylcyclopentan-1-one

In the manner of Example 3, 2-(carboxymethyl)cyclopentan-1-one (Example209) is esterified to provide the subject ester.

EXAMPLE 211 Preparation of 1-acetoxy-2-(carbethoxymethyl)cyclopent-1-ene

In the manner described in Example 10, treatment of2-(carbethoxymethyl)cyclopentan-1-one (Example 210) with aceticanhydride and p-toluenesulfonic acid monohydrate gives an oil, b.p.130°-131° C. (7 mm).

EXAMPLE 212 Preparation of 2-(carbethoxymethyl)cyclopent-2-en-one

In the manner described in Example 13, treatment of1-acetoxy-2-(carbethoxymethyl)cyclopent-1-ene (Example 211) with bromineand subsequent dehydrobromination with lithium bromide-lithium carbonatein N,N-dimethylformamide gives an amber oil. This material is subjectedto chromatography on diatomaceous earth using an n-heptane:methylcellosolve system. Removal of the solvent from hold back volume 4.5-4.7gives an oil which is then further treated with hydroxylaminehydrochloride, sodium acetate in ethanol at room temperature for 18hours to give the desired product; b.p. 71° C. (0.12 mm); λ_(max)^(MeOH) 222 mμ (10,300); λ max 5.75, 5.85, 6.15, 8.65 μ.

EXAMPLE 213 Preparation of ethyl9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate

In the manner described in Example 80,2-(carbethoxymethyl)-2-cyclopentenone (Example 212) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 214 Preparation of2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano-cyclopentane

A mixture of 10.142 g. (0.0362 mole) of2-(carbethoxymethyl)-3-(1-octenyl)cyclopentanone (ethyl9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate, Example 213), 3.49 g.(0.0562 mole) of ethylene glycol, 0.344 g. of p-toluensulfonic acidmonohydrate, and 30 ml. of benzene is refluxed for 4.5 hours withazeotropic removal of water. The mixture is cooled, placed onto a columnof 130 g. of Florisil® in benzene and the ketal is eluted off withbenzene. The filtrate is evaporated to yield 9.53 g. of a colorless oil.

EXAMPLE 215 Preparation of2-(formylmethyl)-3-(1-trans-octenyl)-1,1-dioxolanocyclopentane

To a solution of 1.00 g. (0.00308 mole) of2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 5ml. of heptane at -78° C. and under nitrogen is added dropwise 2.60 ml.of a solution of 25% diisobutylaluminum hydride in hexane. The resultingsolution is stirred at -78° C. for 2.5 hours and then poured into colddilute hydrochloric acid. The organic phase is washed with saturatedbrine, dried (Na₂ SO₄), and evaporated to yield 0.863 g. of a colorlessoil. IR 2695, 1723, 1045, 970 cm⁻¹.

EXAMPLE 216 Preparation of2-(6-carboxy-2-cis-hexenyl)-3-(1-trans-octenyl)-1,1-dioxolanocyclopentane

A mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineraloil) and 5.5 ml. of dimethylsulfoxide is heated to 70° C. until gasevolution ceases under a nitrogen atmosphere. The resulting solution iscooled below room temperature and treated with a solution of 1.400 g.(0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J.Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. ofdimethylsulfoxide. To the resulting red solution is added 0.738 g.(0.00263 mole) of 2-(formylmethyl)-3-(1-trans-octenyl)-1,1-dioxolanocyclopentane in 2 ml. of dimethylsulfoxide and the mixture is stirred atroom temperature for 2.25 hours. The mixture is poured into ice water,sodium hydroxide solution is added to pH 12, and the neutral materialsare extracted with diethyl ether. The basic phase is acidified withdilute hydrochloric acid and is extracted with diethyl ether. Theorganic phase is washed with water and saturated brine, dried (Na₂ SO₄),and evaporated to a semicrystalline mass. The latter is triturated withhot hexane, the solids are filtered off, and the filtrate is evaporatedto yield an oil. IR: 1705, 1040, 970, 722 cm⁻¹.

EXAMPLE 217 Preparation of 9-oxo-5-cis-13-trans-prostadienoic acid

A solution of 0.726 g. of2-(6-carboxy-2-cis-hexenyl)-3-(1-trans-octenyl)-1,1-dioxolanocyclopentane and 19 mg. of p-toluensulfonic acid monohydrate in 30 ml.of acetone is stirred at ambient temperatures for 66 hours. The volatilematerial is removed in vacuo and the residue is passed through a columnof silica gel in chloroform collecting those fractions which containproduct. The solvent is evaporated to yield the subject product as anoil. IR: 1740, 1705, 970, 722 cm⁻¹.

EXAMPLE 218 Preparation of ethyl 9-oxo-5-cis-13-trans-prostadienoate

By the procedure described in Example 195,9-oxo-5-cis-13-trans-prostadienoic acid is esterified with ethyl alcoholto the subject ethyl ester.

EXAMPLES 219-226

Treatment of the 9-oxo-13-trans-prostenoate esters of the followingTable with sodium borohydride in ethanol by the method described inExample 142 is productive of the 9-hydroxy-(mixture of α and βepimers)-prostenoates of the following Table.

                  TABLE XIV                                                       ______________________________________                                                  Starting 9-oxo-                                                     Exam-     prostenoate of                                                      ple       Example       Product                                               ______________________________________                                        219       199           ethyl 9-hydroxy-3-oxa-                                                        trans-prostenoate                                     220       200           ethyl 20-chloro-9-hy-                                                         droxy-3-oxa-13-trans-                                                         prostenoate                                           221       202           ethyl 9-hydroxy-3-oxa-                                                        13-trans-17-cis-pro-                                                          stadienoate                                           222       203           ethyl 9-hydroxy-20-                                                           methyl-3-oxa-13-trans-                                                        prostenoate                                           223       198           ethyl 9-hydroxy-3-thia-                                                       13-trans-prostenoate                                  224       206           ethyl 9-hydroxy-3-thia-                                                       13-trans-17-cis-pro-                                                          stadienoate                                           225       207           ethyl 9-hydroxy-3-thia-                                                       19,20-dinor-13-trans-                                                         prostenoate                                           226       218           ethyl 9-hydroxy-5-cis-                                                        13-trans-prostandieno-                                                        ate                                                   ______________________________________                                    

EXAMPLES 227-244

Saponification of the esters of the following table by the procedure ofExample 151 is productive of the carboxylic acids of this table.

                  TABLE XV                                                        ______________________________________                                        Exam-     Starting Ester                                                      ple       of Example   Product                                                ______________________________________                                        227       198          9-oxo-3-thia-13-trans-                                                        prostenoic acid                                        228       199          9-oxa-13-trans-                                                               prostenoic acid                                        229       200          20-chloro-3-oxa-9-oxa-                                                        13-trans-prostenoic                                                           acid                                                   230       201          20-chloro-3-oxa-9-oxo-                                                        17,18,19-trinor-13-                                                           trans-prostenoic acid                                  231       202          3-oxa-9-oxo-13-trans-                                                         17-cis-prostadienoic                                                          acid                                                   232       203          20-methyl-3-oxa-9-oxo-                                                        13-trans-prostenoic                                                           acid                                                   233       204          20-chloro-9-oxo-3-thia-                                                       13-trans-prostenoic                                                           acid                                                   234       205          20-chloro-9-oxo-3-thia-                                                       17,18,19-trinor-13-                                                           trans-prostenoic acid                                  235       206          9-oxo-3-thia-13-trans-                                                        17-cis-prostadienoic                                                          acid                                                   236       207          9-oxo-3-thia-19,20-di-                                                        nor-13-trans-prostenoic                                                       acid                                                   237       219          9-hydroxy-3-oxa-13-                                                           trans-prostenoic acid                                  238       220          20-chloro-9-hydroxy-3-                                                        oxa-13-trans-proste-                                                          noic acid                                              239       221          9-hydroxy-3-oxa-13-                                                           trans-17-cis-prosta-                                                          dienoic acid                                           240       222          9-hydroxy-20-methyl-                                                          3-oxa-13-trans-proste-                                                        noic acid                                              241       223          9-hydroxy-3-thia-13-                                                          trans-prostenoic acid                                  242       224          9-hydroxy-3-thia-13-                                                          trans-17-cis-prosta-                                                          dienoic acid                                           243       225          9-hydroxy-3-thia-19,-                                                         20-dinor-13-trans-pro-                                                        stenoic acid                                           244       226          9-hydroxy-5-cis-13-                                                           trans-prostadienoic                                                           acid                                                   ______________________________________                                    

We claim:
 1. Compounds of the formula: ##STR25## wherein n is an integerfrom 3 to 8, inclusive; R is lower alkyl; and Q is p-toluenesulfonyloxy.2. The compound according to claim 1 wherein R is methyl, n is 5, and Qis p-toluenesulfonyloxy.
 3. The compound of claim 1 wherein R is methyl,n is 4, and Q is p-toluenesulfonyloxy.